U.S. patent number 9,695,131 [Application Number 15/034,995] was granted by the patent office on 2017-07-04 for substituted uracils as chymase inhibitors.
This patent grant is currently assigned to Bayer Pharma Aktiengesellschaft. The grantee listed for this patent is Bayer Pharma Aktiengesellschaft. Invention is credited to Jens Ackerstaff, Chantal Furstner, Heinrich Meier, Jens Schamberger, Alexander Straub, Hanna Tinel, Katja Zimmermann, Dmitry Zubov.
United States Patent |
9,695,131 |
Furstner , et al. |
July 4, 2017 |
Substituted uracils as chymase inhibitors
Abstract
Substituted uracil derivatives of formula (I), processes for
their preparation, their use alone or in combinations for the
treatment and/or prophylaxis of diseases, and their use for
preparing medicaments for the treatment and/or prophylaxis of
diseases.
Inventors: |
Furstner; Chantal
(Mulheim/Ruhr, DE), Ackerstaff; Jens (Dusseldorf,
DE), Straub; Alexander (Wuppertal, DE),
Meier; Heinrich (Wuppertal, DE), Tinel; Hanna
(Wuppertal, DE), Zimmermann; Katja (Dusseldorf,
DE), Zubov; Dmitry (Remscheid, DE),
Schamberger; Jens (Velbert-Langenberg, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Bayer Pharma Aktiengesellschaft |
Berlin |
N/A |
DE |
|
|
Assignee: |
Bayer Pharma Aktiengesellschaft
(Berlin, DE)
|
Family
ID: |
49582563 |
Appl.
No.: |
15/034,995 |
Filed: |
November 5, 2014 |
PCT
Filed: |
November 05, 2014 |
PCT No.: |
PCT/EP2014/073800 |
371(c)(1),(2),(4) Date: |
May 06, 2016 |
PCT
Pub. No.: |
WO2015/067651 |
PCT
Pub. Date: |
May 14, 2015 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20160244415 A1 |
Aug 25, 2016 |
|
Foreign Application Priority Data
|
|
|
|
|
Nov 8, 2013 [EP] |
|
|
13192183 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
403/10 (20130101); C07D 413/14 (20130101); A61P
13/12 (20180101); C07D 413/10 (20130101); C07D
413/04 (20130101); C07D 413/12 (20130101); C07D
403/14 (20130101); A61P 9/04 (20180101); C07D
417/04 (20130101); A61P 17/00 (20180101); C07D
417/12 (20130101); A61K 31/513 (20130101); A61P
9/12 (20180101); A61P 11/06 (20180101); C07D
239/557 (20130101); C07D 403/04 (20130101); A61K
9/0053 (20130101); C07D 417/14 (20130101); A61K
45/06 (20130101); A61P 11/00 (20180101); A61P
43/00 (20180101); A61K 9/08 (20130101); A61P
9/00 (20180101); C07D 239/54 (20130101); C07D
403/12 (20130101); A61K 9/20 (20130101) |
Current International
Class: |
C07D
403/04 (20060101); A61K 31/513 (20060101); A61K
45/06 (20060101); C07D 403/14 (20060101); C07D
413/14 (20060101); A61K 9/20 (20060101); A61K
9/08 (20060101); A61K 9/00 (20060101); C07D
417/12 (20060101); C07D 417/04 (20060101); C07D
413/12 (20060101); C07D 413/10 (20060101); C07D
417/14 (20060101); C07D 239/54 (20060101); C07D
403/10 (20060101); C07D 403/12 (20060101); C07D
239/557 (20060101); C07D 413/04 (20060101) |
Field of
Search: |
;514/269,274,393 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0936216 |
|
Aug 1999 |
|
EP |
|
10195063 |
|
Jul 1998 |
|
JP |
|
96/33974 |
|
Oct 1996 |
|
WO |
|
00/06568 |
|
Feb 2000 |
|
WO |
|
00/06569 |
|
Feb 2000 |
|
WO |
|
01/19355 |
|
Mar 2001 |
|
WO |
|
01/19776 |
|
Mar 2001 |
|
WO |
|
01/19778 |
|
Mar 2001 |
|
WO |
|
01/19780 |
|
Mar 2001 |
|
WO |
|
02/42301 |
|
May 2002 |
|
WO |
|
02/070462 |
|
Sep 2002 |
|
WO |
|
02/070510 |
|
Sep 2002 |
|
WO |
|
03/095451 |
|
Nov 2003 |
|
WO |
|
2007/120339 |
|
Oct 2007 |
|
WO |
|
2007/150011 |
|
Dec 2007 |
|
WO |
|
2008/056257 |
|
May 2008 |
|
WO |
|
2008/103277 |
|
Aug 2008 |
|
WO |
|
2009/049112 |
|
Apr 2009 |
|
WO |
|
2009/156182 |
|
Dec 2009 |
|
WO |
|
2010/019903 |
|
Feb 2010 |
|
WO |
|
2013/074633 |
|
May 2013 |
|
WO |
|
Other References
Abdelaal, et al., "Synthesis of 1-[3-Methyl-2(3H)-benzazolon-5- or
6-yl]-4-{4-[cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-l-yl-methyl)-1,3-di-
oxolan-4-yl]methyleneoxyphenyl}piperazines", J. Heterocyclic Chem.,
29, 1992, pp. 1069-1076. cited by applicant .
Artico, et al., "Research on Compounds with Antiblastic Activity",
Farmaco Sci. Ed. 179, 1969, 15 pages. cited by applicant .
Bacani, et al., "Chymase: A New Pharmacologic Target in
Cardiovascular Disease", Cardiology in Review, 14(4), Jul./Aug.
2006, pp. 187-193. cited by applicant .
Dogrell, "Therapeutic Potential of Non-peptide Chymase Inhibitors",
Expert Opin. Ther. Patents 18, 2008, pp. 485-499. cited by
applicant .
Fleming, "Signaling by the Angiotensin-Converting Enzyme",
Circulation Research, Apr. 14, 2006, pp. 887-896. cited by
applicant .
Huang, et al., "Chymase is Upregulated in Diabetic Nephropathy:
Implications for an Alternative Pathway of Angiotensin II-Mediated
Diabetic Renal and Vascular Disease", Journal of the American
Society of Nephrology, 14, 2003, pp. 1738-1747. cited by applicant
.
Hughes, "Progress in the Mitsunobu Reaction. A Review", Organic
Preparations and Procedures International: The New Journal for
Organic Synthesis, 28(2), 1996, pp. 127-164. cited by applicant
.
Hughes, "The Mitsunobu Reaction", Chapter 2, Organic Reactions, 42,
1992, pp. 335-656. cited by applicant .
Jin, et al., "An Antiarrhythmic Effect of Chymase Inhibitor After
Myocardial Infarction", Pharmacol. Exp. Ther. 309, 2004, pp.
409-417. cited by applicant .
Jin, et al., "Beneficial effects of cardiac chymase inhibition
during the acute phase of myocardial infarction", Life Sciences,
71, 2002, pp. 437-446. cited by applicant .
Kovanen, et al., "Infiltrates of Activated Mast Cells at the Site
of Coronary Atheromatous Erosion or Rupture in Myocardial
Infarction", Circulation, 92(5), Sep. 1, 1995, pp. 1084-1088. cited
by applicant .
Libby, et al., "Mast Cells as Mediators and Modulators of
Atherogenesis", Circulation 115, 2007, pp. 2555-2558. cited by
applicant .
Lucero, et al., "Synthesis and anti-HSV-1 activity of quinolonic
acyclovir analogues", Bioorganic & Medicinal Chemistry Letters,
16, 2006, pp. 1010-1013. cited by applicant .
Matusumoto, et al., "Chymase Inhibition Prevents Cardiac Fibrosis
and Improves Diastolic Dysfunction in the Progression of Heart
Failure", Circulation, May 27, 2003, pp. 2555-2558. cited by
applicant .
McPherson, et al., "Chymase-like Angiotensin II-Generating Activity
in End-Stage Human Autosomal Dominant Polycystic Kidney Disease",
Journal of the American Society of Nephrology, 15, 2004, pp.
493-500. cited by applicant .
Miyazaki, et al., "Pathological roles of angiotensin II produced by
mast cell chymase and the effects of chymase inhibition in animal
models", Pharmacology & Therapeutics, 112, 2006, pp. 668-676.
cited by applicant .
Mulvany, et al., "Contractile Properties of Small Arterial
Resistance Vessels in Spontaneously Hypertensive and Normotensive
Rats", Circulation Research, 41(1), Jul. 1977, pp. 19-26. cited by
applicant .
Senda, et al., "Pyrimidine Derivatives and Related Compounds.
XVI.1) Synthesis of 1,3-Disubstituted5-Cyanouracil Derivatives and
Related Compounds", Chem. Pharm. Bull., vol. 20(7), 1972, pp.
1380-1388. cited by applicant .
Shiota, et al., "Cardiac mast cells in the transition to heart
failure: innocent bystanders or key actors?", Journal of
Hypertension, 21, 2003, pp. 1823-1825. cited by applicant .
Stabile, et al., "Mild, convenient and versatile Cu-mediated
synthesis of N-aryl-2-imidazolidinones", Tetrahedron Letters,
51(24), 2010, pp. 3232-3235. cited by applicant .
Takai, et al., "An Orally Active Chymase Inhibitor, BCEAB,
Supresses Heart Chymase Activity in the Hamster", Japanese Journal
of Pharmacology, 86, 2001, pp. 124-126. cited by applicant .
Van Henegouwen, et al., "First Total Synthesis of ent-Gelsedine via
a Novel Iodide-Promoted Allene N-Acyliminium Ion Cyclization",
Journal of Organic Chemistry, 65(24), 2000, pp. 8317-8325. cited by
applicant .
Zanini, et al., "Chymase-positive mast cells play a role in the
vascular component of airway remodeling in asthma", Journal of
Allergy Clinical Immunology, 120(2), Aug. 2007, pp. 329-333. cited
by applicant .
International Bureau of WIPO, International Preliminary Report on
Patentability (with English translation) for International Patent
Application No. PCT/EP2014/073800, May 10, 2016, 7 pages. cited by
applicant .
European Patent Office, International Search Report (with English
translation) for International Patent Application No.
PCT/EP2014/073800, Dec. 12, 2014, 5 pages. cited by applicant .
European Patent Office, Written Opinion (with English translation)
for International Patent Application No. PCT/EP2014/073800, May 14,
2015, 13 pages. cited by applicant.
|
Primary Examiner: Bakshi; Pancham
Attorney, Agent or Firm: Morrison & Foerster LLP
Claims
The invention claimed is:
1. A compound of the formula (I) ##STR00159## in which R.sup.1
represents a group of the formula ##STR00160## where represents the
point of attachment to the uracil group, m represents 0 or 1,
L.sup.1A represents a bond or (C.sub.1-C.sub.4)-alkanediyl, in
which (C.sub.1-C.sub.4)-alkanediyl may be substituted by 1 to 3
substituents independently of one another selected from the group
consisting of fluorine, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy,
R.sup.5 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6
represents hydrogen or (C.sub.1-C.sub.4)-alkyl, in which
(C.sub.1-C.sub.4)-alkyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
fluorine, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy and
(C.sub.1-C.sub.4)-alkoxy, or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached form a 3- to 7-membered
carbocycle, R.sup.7 represents hydrogen, cyano,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, R.sup.2 represents a group of the
formula ##STR00161## where ** represents the point of attachment to
the uracil nitrogen atom, A represents CH.sub.2--,
--CH.sub.2--CH.sub.2--, --O--CH.sub.2-## or oxygen, in which ##
represents the point of attachment to the phenyl ring, n represents
a number 0, 1 or 2, R.sup.10 represents hydrogen, halogen,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
difluoromethoxy, trifluoromethoxy or (C.sub.1-C.sub.4)-alkoxy,
R.sup.3 represents ##STR00162## in which # represents the point of
attachment to the uracil nitrogen atom, the ring Q represents 5- to
7-membered heterocyclyl or 5- or 6-membered heteroaryl, in which 5-
to 7-membered heterocyclyl may be substituted by 1 to 4
substituents independently selected from the group of halogen,
difluoromethyl, trifluoromethyl, trideuteromethyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, oxo,
hydroxyl, (C.sub.1-C.sub.4)-alkylcarbonyl,
(C.sub.1-C.sub.4)-alkoxycarbonyl, aminocarbonyl and
(C.sub.1-C.sub.4)-alkyl sulfonyl, in which 5- or 6-membered
heteroaryl may be substituted by 1 to 2 substituents independently
of one another selected from the group consisting of
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
(C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
aminocarbonyl and (C.sub.1-C.sub.4)-alkylsulfonyl, and in which two
(C.sub.1-C.sub.6)-alkyl radicals attached to a carbon atom of 5- to
7-membered heterocyclyl together with the carbon atom to which they
are attached may form a 3- to 6-membered carbocycle, R.sup.25
represents halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, p represents a number 0, 1, 2 or 3, and
R.sup.4 represents hydrogen, and the salts, solvates and solvates
of the salts thereof.
2. The compound of claim 1, wherein R.sup.1 represents a group of
the formula ##STR00163## where * represents the point of attachment
to the uracil group, m represents 0 or 1, L.sup.1A represents a
bond or (C.sub.1-C.sub.4)-alkanediyl, R.sup.5 represents hydrogen
or (C.sub.1-C.sub.4)-alkyl, R.sup.6 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.4)-alkyl may be
substituted by 1 or 2 substituents independently of one another
selected from the group consisting of fluorine, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy, or
R.sup.5 and R.sup.6 together with the carbon atoms to which they
are attached form a 3- to 6-membered carbocycle, R.sup.7 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyano,
(C.sub.3-C.sub.6)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, R.sup.2 represents a group of the
formula ##STR00164## where ** represents the point of attachment to
the uracil nitrogen atom, A represents CH.sub.2-- or
--CH.sub.2--CH.sub.2--, n represents a number 0, 1 or 2, R.sup.10
represents hydrogen, fluorine, chlorine, difluoromethyl,
trifluoromethyl or methyl, R.sup.3 represents a group of the
formula ##STR00165## where # represents the point of attachment to
the uracil nitrogen atom, G.sup.1 represents C.dbd.O or SO.sub.2,
G.sup.2 represents CR.sup.27AR.sup.27B, NR.sup.28, O or S, where
R.sup.27A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or
hydroxy, R.sup.27B represents hydrogen, fluorine, chlorine,
(C.sub.1-C.sub.4)-alkyl or trifluoromethyl, or R.sup.27A and
R.sup.27B together with the carbon atom to which they are attached
form a 3- to 6-membered carbocycle, R.sup.28 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, R.sup.25
represents fluorine or methyl, p represents a number 0 or 1,
R.sup.26 represents hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, R.sup.4 represents hydrogen, and the
salts, solvates and solvates of the salts thereof.
3. The compound of claim 1 wherein R.sup.1 represents a group of
the formula ##STR00166## where * represents the point of attachment
to the uracil group, m represents 0 or 1, L.sup.1A represents a
bond, methanediyl or ethanediyl, R.sup.5 represents hydrogen,
R.sup.6 represents hydrogen or methyl, in which methyl may be
substituted by hydroxy, or R.sup.5 and R.sup.6 together with the
carbon atom to which they are attached form a 3- to 5-membered
carbocycle, R.sup.7 represents hydrogen, cyano, hydroxycarbonyl,
methoxycarbonyl or ethoxycarbonyl, R.sup.2 represents a group of
the formula ##STR00167## where ** represents the point of
attachment to the uracil nitrogen atom, A represents --CH.sub.2--
or --CH.sub.2--CH.sub.2--, R.sup.10 represents chlorine or
trifluoromethyl, R.sup.3 represents a group of the formula
##STR00168## where # represents the point of attachment to the
uracil nitrogen atom, R.sup.4 represents hydrogen, and the salts,
solvates and solvates of the salts thereof.
4. A method of preparing the compound of claim 1 wherein [A] a
compound of the formula (II) ##STR00169## in which T.sup.1A
represents (C.sub.1-C.sub.4)-alkyl, T.sup.2 represents
(C.sub.1-C.sub.4)-alkyl, T.sup.3 represents
(C.sub.1-C.sub.4)-alkyl, is reacted in an inert solvent, optionally
in the presence of a suitable base, with a compound of the formula
(III) R.sup.3--NH.sub.2 (III), in which R.sup.3 has the meaning
given above to give a compound of the formula (IV) ##STR00170## in
which T.sup.1A and R.sup.3 each have the meanings given above, this
is then reacted in an inert solvent, in the presence of a suitable
base, with a compound of the formula (V) X.sup.1--R.sup.2 (V) in
which R.sup.2 has the meaning given above and X.sup.1 represents
hydroxy or a suitable leaving group, in particular chlorine,
bromine or iodine, to give a compound of the formula (VI)
##STR00171## in which T.sup.1A, R.sup.2 and R.sup.3 each have the
meanings given above, the compound of the formula (VI) is then
hydrolyzed in an inert solvent in the presence of a suitable acid
or base to give a compound of the formula (VII) ##STR00172## in
which T.sup.1B represents hydrogen and in which R.sup.2 and R.sup.3
each have the meanings given above, and then in an inert solvent
with a compound of the formula (VIII) ##STR00173## converted into a
compound of the formula (I-1) ##STR00174## in which R.sup.2,
R.sup.3, R.sup.5, R.sup.6, R.sup.7, L.sup.1A and m each have the
meanings given above, or [B] a compound of the formula (IX)
##STR00175## in which T.sup.1A, T.sup.2 and T.sup.3 each have the
meanings mentioned above, is converted in an inert solvent or else
without solvent with a compound of the formula (III) into a
compound of the formula (X) ##STR00176## in which R.sub.3, T.sup.1A
and T.sup.3 each have the meanings given above, this is
subsequently reacted in an inert solvent with chlorosulfonyl
isocyanate to give a compound of the formula (IV) and this is
subsequently converted analogously to process [A] into a compound
of the formula (I-1), or [C] a compound of the formula (XI)
##STR00177## in which T.sup.2 represents (C.sub.1-C.sub.4)-alkyl,
T.sup.3 represents (C.sub.1-C.sub.4)-alkyl and R.sup.4 has the
meaning given above, is reacted in an inert solvent, optionally in
the presence of a suitable base, with a compound of the formula
(III) to give a compound of the formula (XII) ##STR00178## in which
R.sup.3 and R.sup.4 each have the meanings given above, and this is
then, by reaction with a compound of the formula (V) in an inert
solvent, if appropriate in the presence of a suitable base,
converted into a compound of the formula (I-2) ##STR00179## in
which R.sup.2, R.sup.3 and R.sup.4 each have the meanings given
above, or [D] a compound of the formula (I-2) is converted with an
azide source in the presence of a catalyst in an inert solvent into
a compound of the formula (I-3) ##STR00180## in which R.sup.2,
R.sup.3 and R.sup.4 each have the meanings given above, or [E] a
compound of the formula (I-2) is converted with hydroxylamine into
a compound of the formula (XIII) ##STR00181## in which R.sup.2 and
R.sup.3 each have the meanings given above, and then in an inert
solvent with a carbonyl donor or a thiocarbonyl donor, if
appropriate in the presence of a base, to give a compound of the
formula (I-4) ##STR00182## in which R.sup.2 and R.sup.3 each have
the meanings given above and in which Q* represents oxygen or
sulfur, any protecting groups are detached and/or the compounds of
the formulae (I-1), (I-2), (I-3) and (I-4) are, where appropriate,
converted with the appropriate (i) solvents and/or (ii) bases or
acids to the solvates, salts and/or solvates of the salts thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. national phase application of
International Patent Application No. PCT/EP2014/073800, filed Nov.
5, 2014 and titled SUBSTITUTED URACILS AS CHYMASE INHIBITORS, which
claims priority to European Patent Application No. 13192183.5,
filed Nov. 8, 2013 and titled SUBSTITUTED URACILS AS CHYMASE
INHIBITORS, the contents of both of which are incorporated herein
by reference in their entirety.
The present application relates to novel substituted uracil
derivatives, to processes for their preparation, to their use alone
or in combinations for the treatment and/or prophylaxis of
diseases, and to their use for preparing medicaments for the
treatment and/or prophylaxis of diseases.
Chymase is a chymotrypsin-like serine protease which is stored as a
macromolecular complex with heparin proteoglycans in secretory
vesicles of mast cells. After activation of the mast cells, chymase
is released into the extracellular matrix and activated.
Activated mast cells play an important role in healing wounds and
in inflammation processes, for example fibrosis of wounds,
angiogenesis and cardiac remodelling (Miyazaki et al., Pharmacol.
Ther. 112 (2006), 668-676; Shiota et al., J. Hypertens. 21 (2003),
1823-1825). An increase in the number of mast cells has been
observed in the event of heart failure, myocardial infarction and
ischaemia, in human atherosclerotic plaques and in abdominal aortic
aneurysms (Kovanen et al., Circulation 92 (1995), 1084-1088; Libby
and Shi, Circulation 115 (2007), 2555-2558; Bacani and Frishman,
Cardiol. Rev. 14(4) (2006), 187-193). Chymase-positive mast cells
can also play an important role in the vascular remodelling of the
respiratory pathways in the event of asthma and chronic obstructive
pulmonary disease. An increased number of mast cells has been found
in endobronchial biopsies of asthma patients (Zanini et al., J.
Allergy Clin. Immunol. 120 (2007), 329-333). Moreover, chymase is
suspected of being partly responsible for the genesis of many renal
disorders, such as diabetic nephropathy and polycystic kidney
disease (Huang et al., J. Am. Soc. Nephrol. 14(7) (2003),
1738-1747; McPherson et al., J. Am. Soc. Nephrol. 15(2) (2004),
493-500).
Chymase is predominantly involved in the production of angiotensin
II in the heart, in the artery wall and in the lung, whereas the
angiotensin-converting enzyme is responsible for the formation of
the peptide in the circulation system (Fleming I., Circ. Res. 98
(2006), 887-896). In addition, chymase cleaves a number of other
substrates of pathological significance. Chymase leads to
degradation of extracellular matrix proteins, such as fibronectin,
procollagen and vitronectin, and to the breakoff of focal
adhesions. It brings about activation and release of TGF.beta. from
its latent form, which plays an important role in the genesis of
cardiac hypertrophy and cardiac fibrosis. The enzyme has
atherogenic action, by degrading apolipoproteins and preventing the
absorption of cholesterol by HDL. The action of chymase leads to
release and activation of the cytokine interleukin 1 with its
pro-inflammatory properties. Furthermore, it contributes to
production of endothelin 1 (Bacani and Frishman, Cardiol. Rev.
14(4) (2006), 187-193). An accumulation of chymase-positive mast
cells has been found in biopsies of patients having atopic
dermatitis, Crohn's disease, chronic hepatitis and hepatic
cirrhosis, and also idiopathic interstitial pneumonia (Dogrell S.
A., Expert Opin. Ther. Patents 18 (2008), 485-499).
The possibility of using chymase inhibitors for the treatment of
different diseases has been demonstrated in numerous studies
involving animal experimentation. Inhibition of chymase can be
useful for the treatment of myocardial infarction. Jin et al.
(Pharmacol. Exp. Ther. 309 (2004), 409-417) showed that a ligature
of the coronary artery in dogs led to ventricular arrhythmias and
elevated production of angiotensin II and chymase activity in the
heart. Intravenous administration of the chymase inhibitor
TY-501076 reduced chymase activity and the angiotensin II
concentration in the plasma, and suppressed the occurrence of
arrhythmias. A positive effect of chymase inhibition was shown in
an in vivo model for myocardial infarction in hamsters. Treatment
of the animals with the chymase inhibitor BCEAB reduced chymase
activity, improved haemodynamics and reduced mortality (Jin et al.,
Life Sci. 71 (2002), 437-446). In the cardiomyopathic Syrian
hamster, where the number of mast cells in the heart is elevated,
oral treatment of the animals with the chymase inhibitor reduced
cardiac fibrosis by 50% (Takai et al., Jpn. J. Pharmacol. 86
(2001), 124-126). In a tachycardia-induced heart failure model in
dogs, chymase inhibition with SUN-C82257 led to reduction in the
number of mast cells and in fibrosis in the heart. In addition, the
diastolic function of the heart was improved after the treatment
(Matsumoto et al., Circulation 107 (2003), 2555-2558).
Inhibition of chymase thus constitutes an effective principle in
the treatment of cardiovascular disorders, inflammation and
allergic disorders, and various fibrotic disorders.
WO 2007/150011 and WO 2009/049112 disclose a process for preparing
pyrimidinetriones with glycine substituents. WO 2008/056257
describes triazinediones as GABA-B receptor modulators for
treatment of CNS disorders. WO 2008/103277 discloses various
nitrogen heterocycles for treatment of cancer. WO 2009/156182
describes uracil derivatives for suppression or reduction of
resistance development in the course of cytostatic treatment.
JP10195063 describes uracil derivatives as leukotriene antagonists,
WO 2013/074633 uracil derivatives as inhibitors of the tyrosine
kinases AXL and c-MET.
It was an object of the present invention to provide novel
substances which act as inhibitors of chymase and are suitable as
such for treatment and/or prophylaxis of disorders, especially
cardiovascular disorders.
The present invention relates to compounds of the general formula
(I)
##STR00001## in which R.sup.1 represents cyano, 5- to 7-membered
heterocyclyl or 5- or 6-membered heteroaryl, where 5- to 7-membered
heterocyclyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
oxo, (C.sub.1-C.sub.4)-alkyl and halogen, and where 5- or
6-membered heteroaryl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
(C.sub.1-C.sub.4)-alkyl, hydroxy and halogen, or R.sup.1 represents
a group of the formula
##STR00002## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond or
(C.sub.1-C.sub.4)-alkanediyl, in which (C.sub.1-C.sub.4)-alkanediyl
may be substituted by 1 to 3 substituents independently of one
another selected from the group consisting of fluorine,
trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy,
R.sup.5 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6
represents hydrogen or (C.sub.1-C.sub.4)-alkyl, in which
(C.sub.1-C.sub.4)-alkyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
fluorine, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy and
(C.sub.1-C.sub.4)-alkoxy, or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached form a 3- to 7-membered
carbocycle, R.sup.7 represents hydrogen, cyano,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, or R.sup.1 represents a group of
the formula
##STR00003## where *** represents the point of attachment to the
uracil group, R.sup.2 represents a group of the formula
##STR00004## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --O--CH.sub.2-## or oxygen, in which ##
represents the point of attachment to the phenyl ring, n represents
a number 0, 1 or 2, R.sup.10 represents hydrogen, halogen,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
difluoromethoxy, trifluoromethoxy or (C.sub.1-C.sub.4)-alkoxy,
R.sup.11A represents hydrogen or deuterium, R.sup.11B represents
hydrogen, deuterium or (C.sub.1-C.sub.4)-alkyl, R.sup.12 represents
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl, difluoromethyl or
trifluoromethyl, R.sup.13 represents halogen,
(C.sub.1-C.sub.4)-alkyl, difluoromethyl or trifluoromethyl,
R.sup.14 represents hydrogen or halogen, R.sup.15 represents
hydrogen or halogen, R.sup.3 represents
##STR00005## where # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, R.sup.18 represents
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy,
(C.sub.1-C.sub.4)-alkylthio, (C.sub.1-C.sub.4)-alkylsulfinyl,
(C.sub.1-C.sub.4)-alkylsulfonyl or --N(R.sup.21R.sup.22), in which
(C.sub.1-C.sub.4)-alkoxy may be substituted by a substituent
independently of one another selected from the group consisting of
hydroxy, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.4)-alkylamino, di-(C.sub.1-C.sub.4)-alkylamino,
aminocarbonyl, mono-(C.sub.1-C.sub.4)-alkylaminocarbonyl and
di-(C.sub.1-C.sub.4)-alkylaminocarbonyl, where R.sup.21 represents
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl or
(C.sub.1-C.sub.4)-alkylaminocarbonyl, in which
(C.sub.1-C.sub.4)-alkylaminocarbonyl may be substituted by hydroxy
or (C.sub.1-C.sub.4)-alkoxy, R.sup.22 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, or R.sup.18 represents 4- to 7-membered
heterocyclyl or 5- to 6-membered heteroaryl, in which 4- to
7-membered heterocyclyl may be substituted by 1 to 3 substituents
independently of one another selected from the group consisting of
halogen, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy, oxo,
amino and (C.sub.1-C.sub.4)-alkoxycarbonyl, in which
(C.sub.1-C.sub.4)-alkyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
halogen, hydroxy and --N(R.sup.23R.sup.24), in which R.sup.23
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkylcarbonyl, in which R.sup.24 represents
hydrogen or (C.sub.1-C.sub.4)-alkyl, in which 5- to 6-membered
heteroaryl may be substituted by 1 or 2 substituents independently
of one another selected from the group consisting of halogen,
trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy, amino and
(C.sub.1-C.sub.4)-alkoxycarbonyl, in which (C.sub.1-C.sub.4)-alkyl
may be substituted by 1 or 2 substituents independently of one
another selected from the group consisting of halogen, hydroxy and
--N(R.sup.23R.sup.24), in which R.sup.23 represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkylcarbonyl, in
which R.sup.24 represents hydrogen or (C.sub.1-C.sub.4)-alkyl,
R.sup.19 represents hydrogen, halogen, cyano,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkoxy, R.sup.20
represents hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, or R.sup.3 represents
##STR00006## in which # represents the point of attachment to the
uracil nitrogen atom, the ring Q represents 5- to 7-membered
heterocyclyl or 5- or 6-membered heteroaryl, in which 5- to
7-membered heterocyclyl may be substituted by 1 to 4 substituents
independently selected from the group of halogen, difluoromethyl,
trifluoromethyl, trideuteromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, oxo, hydroxyl,
(C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
aminocarbonyl and (C.sub.1-C.sub.4)-alkylsulfonyl, in which 5- or
6-membered heteroaryl may be substituted by 1 to 2 substituents
independently of one another selected from the group consisting of
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
(C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
aminocarbonyl and (C.sub.1-C.sub.4)-alkylsulfonyl, and in which two
(C.sub.1-C.sub.6)-alkyl radicals attached to a carbon atom of 5- to
7-membered heterocyclyl together with the carbon atom to which they
are attached may form a 3- to 6-membered carbocycle, R.sup.25
represents halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, p represents a number 0, 1, 2 or 3,
R.sup.4 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, and the
salts, solvates and solvates of the salts thereof.
The present invention relates to compounds of the general formula
(I) in which R.sup.1 represents cyano, 5- to 7-membered
heterocyclyl or 5- or 6-membered heteroaryl, where 5- to 7-membered
heterocyclyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
oxo, (C.sub.1-C.sub.4)-alkyl and halogen, and where 5- or
6-membered heteroaryl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
(C.sub.1-C.sub.4)-alkyl, hydroxy and halogen, or R.sup.1 represents
a group of the formula
##STR00007## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond or
(C.sub.1-C.sub.4)-alkanediyl, in which (C.sub.1-C.sub.4)-alkanediyl
may be substituted by 1 to 3 substituents independently of one
another selected from the group consisting of fluorine,
trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy,
R.sup.5 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.6
represents hydrogen or (C.sub.1-C.sub.4)-alkyl, in which
(C.sub.1-C.sub.4)-alkyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
fluorine, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy and
(C.sub.1-C.sub.4)-alkoxy, or R.sup.5 and R.sup.6 together with the
carbon atoms to which they are attached form a 3- to 7-membered
carbocycle, R.sup.7 represents hydrogen, cyano,
(C.sub.3-C.sub.7)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, R.sup.2 represents a group of the
formula
##STR00008## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2--,
--CH.sub.2--CH.sub.2--, --O--CH.sub.2-## or oxygen, in which ##
represents the point of attachment to the phenyl ring, n represents
a number 0, 1 or 2, R.sup.10 represents hydrogen, halogen,
difluoromethyl, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl,
difluoromethoxy, trifluoromethoxy or (C.sub.1-C.sub.4)-alkoxy,
R.sup.11A represents hydrogen or deuterium, R.sup.11B represents
hydrogen, deuterium or (C.sub.1-C.sub.4)-alkyl, R.sup.12 represents
hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl, difluoromethyl or
trifluoromethyl, R.sup.13 represents halogen,
(C.sub.1-C.sub.4)-alkyl, difluoromethyl or trifluoromethyl,
R.sup.14 represents hydrogen or halogen, R.sup.15 represents
hydrogen or halogen, R.sup.3 represents
##STR00009## where # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, R.sup.18 represents
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy,
(C.sub.1-C.sub.4)-alkylthio, (C.sub.1-C.sub.4)-alkylsulfinyl,
(C.sub.1-C.sub.4)-alkylsulfonyl or --N(R.sup.21R.sup.22), in which
(C.sub.1-C.sub.4)-alkoxy may be substituted by a substituent
independently of one another selected from the group consisting of
hydroxy, (C.sub.1-C.sub.4)-alkoxycarbonyl, amino,
mono-(C.sub.1-C.sub.4)-alkylamino, di-(C.sub.1-C.sub.4)-alkylamino,
aminocarbonyl, mono-(C.sub.1-C.sub.4)-alkylaminocarbonyl and
di-(C.sub.1-C.sub.4)-alkylaminocarbonyl, where R.sup.21 represents
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxycarbonyl or
(C.sub.1-C.sub.4)-alkylaminocarbonyl, in which
(C.sub.1-C.sub.4)-alkylaminocarbonyl may be substituted by hydroxy
or (C.sub.1-C.sub.4)-alkoxy, R.sup.22 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, or R.sup.18 represents 4- to 7-membered
heterocyclyl or 5- to 6-membered heteroaryl, in which 4- to
7-membered heterocyclyl may be substituted by 1 to 3 substituents
independently of one another selected from the group consisting of
halogen, trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy, oxo,
amino and (C.sub.1-C.sub.4)-alkoxycarbonyl, in which
(C.sub.1-C.sub.4)-alkyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
halogen, hydroxy and --N(R.sup.23R.sup.24), in which R.sup.23
represents hydrogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkylcarbonyl, in which R.sup.24 represents
hydrogen or (C.sub.1-C.sub.4)-alkyl, in which 5- to 6-membered
heteroaryl may be substituted by 1 or 2 substituents independently
of one another selected from the group consisting of halogen,
trifluoromethyl, (C.sub.1-C.sub.4)-alkyl, hydroxy, amino and
(C.sub.1-C.sub.4)-alkoxycarbonyl, in which (C.sub.1-C.sub.4)-alkyl
may be substituted by 1 or 2 substituents independently of one
another selected from the group consisting of halogen, hydroxy and
--N(R.sup.23R.sup.24), in which R.sup.23 represents hydrogen,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkylcarbonyl, in
which R.sup.24 represents hydrogen or (C.sub.1-C.sub.4)-alkyl,
R.sup.19 represents hydrogen, halogen, cyano,
(C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkoxy, R.sup.20
represents hydrogen, halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, or R.sup.3 represents
##STR00010## in which # represents the point of attachment to the
uracil nitrogen atom, the ring Q represents 5- to 7-membered
heterocyclyl or 5- or 6-membered heteroaryl, in which 5- to
7-membered heterocyclyl and 5- or 6-membered heteroaryl may be
substituted by 1 to 4 substituents independently of one another
selected from the group consisting of halogen, difluoromethyl,
trifluoromethyl, trideuteromethyl, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, oxo, hydroxyl,
(C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
aminocarbonyl and (C.sub.1-C.sub.4)-alkylsulfonyl, in which 5- or
6-membered heteroaryl may be substituted by 1 to 2 substituents
independently of one another selected from the group consisting of
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, hydroxy,
(C.sub.1-C.sub.4)-alkylcarbonyl, (C.sub.1-C.sub.4)-alkoxycarbonyl,
aminocarbonyl and (C.sub.1-C.sub.4)-alkylsulfonyl, and in which two
(C.sub.1-C.sub.6)-alkyl radicals attached to a carbon atom of 5- to
7-membered heterocyclyl together with the carbon atom to which they
are attached may form a 3- to 6-membered carbocycle, R.sup.25
represents halogen, (C.sub.1-C.sub.4)-alkyl or
(C.sub.1-C.sub.4)-alkoxy, p represents a number 0, 1, 2 or 3,
R.sup.4 represents hydrogen or (C.sub.1-C.sub.4)-alkyl, and the
salts, solvates and solvates of the salts thereof.
Compounds of the invention are the compounds of the formula (I) and
the salts, solvates and solvates of the salts thereof, the
compounds that are encompassed by formula (I) and are of the
formulae given below and the salts, solvates and solvates of the
salts thereof and the compounds that are encompassed by the formula
(I) and are mentioned below as embodiments and the salts, solvates
and solvates of the salts thereof if the compounds that are
encompassed by the formula (I) and are mentioned below are not
already salts, solvates and solvates of the salts.
The compounds of the invention may, depending on their structure,
exist in different stereoisomeric forms, i.e. in the form of
configurational isomers or else, if appropriate, of conformational
isomers (enantiomers and/or diastereomers, including those in the
case of atropisomers). The present invention therefore encompasses
the enantiomers and diastereomers and the respective mixtures
thereof. It is possible to isolate the stereoisomerically
homogeneous constituents from such mixtures of enantiomers and/or
diastereomers in a known manner.
If the compounds of the invention can occur in tautomeric forms,
the present invention encompasses all the tautomeric forms.
Preferred salts in the context of the present invention are
physiologically acceptable salts of the compounds according to the
invention. Also encompassed are salts which are not themselves
suitable for pharmaceutical applications but can be used, for
example, for isolation or purification of the compounds of the
invention.
Physiologically acceptable salts of the compounds according to the
invention include acid addition salts of mineral acids, carboxylic
acids and sulfonic acids, for example salts of hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic
acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic
acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic
acid, propionic acid, lactic acid, tartaric acid, malic acid,
citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the inventive compounds also
include salts of conventional bases, by way of example and with
preference alkali metal salts (e.g. sodium and potassium salts),
alkaline earth metal salts (e.g. calcium and magnesium salts) and
ammonium salts derived from ammonia or organic amines having 1 to
16 carbon atoms, by way of example and with preference ethylamine,
diethylamine, triethylamine, ethyldiisopropylamine,
monoethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine,
N-methylmorpholine, arginine, lysine, ethylenediamine and
N-methylpiperidine.
Solvates in the context of the invention are described as those
forms of the compounds of the invention which form a complex in the
solid or liquid state by coordination with solvent molecules.
Hydrates are a specific form of the solvates in which the
coordination is with water. Solvates preferred in the context of
the present invention are hydrates.
The present invention additionally also encompasses prodrugs of the
compounds of the invention. The term "prodrugs" encompasses
compounds which for their part may be biologically active or
inactive but are converted during their residence time in the body
into compounds according to the invention (for example by
metabolism or hydrolysis).
In the context of the present invention, unless specified
otherwise, the substituents are defined as follows:
Alkyl in the context of the invention is a straight-chain or
branched alkyl radical having 1 to 4 carbon atoms. The following
may be mentioned by way of example and by way of preference:
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl
and tert-butyl.
Alkylcarbonyloxy in the context of the invention is a
straight-chain or branched alkylcarbonyl radical which is attached
via an oxygen atom and carries 1 to 4 carbon atoms in the alkyl
chain. The following may be mentioned by way of example and by way
of preference: methylcarbonyloxy, ethylcarbonyloxy,
n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy,
isobutylcarbonyloxy and tert-butylcarbonyloxy.
Alkoxy in the context of the invention is a straight-chain or
branched alkoxy radical 1 to 4 carbon atoms. The following may be
mentioned by way of example and by way of preference: methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
Alkoxycarbonyl in the context of the invention is a straight-chain
or branched alkoxy radical having 1 to 4 carbon atoms and a
carbonyl group attached to the oxygen. Preference is given to a
linear or branched alkoxycarbonyl radical having 1 to 4 carbon
atoms in the alkoxy group. The following may be mentioned by way of
example and by way of preference: methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
Alkoxycarbonylamino in the context of the invention is an amino
group having a linear or branched alkoxycarbonyl substituent which
has 1 to 4 carbon atoms in the alkyl chain and is attached to the
nitrogen atom via the carbonyl group. The following may be
mentioned by way of example and by way of preference:
methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,
n-butoxycarbonylamino, isobutoxycarbonylamino and
tert-butoxycarbonylamino.
Alkylthio in the context of the invention is a linear or branched
alkyl radical which has 1 to 4 carbon atoms and is bonded via a
sulfur atom. The following may be mentioned by way of example and
by way of preference: methylthio, ethylthio, n-propylthio,
isopropylthio, 1-methylpropylthio, n-butylthio, iso-butylthio and
tert-butylthio.
Alkylsulfinyl in the context of the invention is a straight-chain
or branched alkyl radical having 1 to 4 carbon atoms which is
attached via a sulfoxide group. The following may be mentioned by
way of example and by way of preference: methylsulfinyl,
ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl
and tert-butylsulfinyl.
Alkylsulfonyl in the context of the invention is a straight-chain
or branched alkyl radical which has 1 to 4 carbon atoms and is
bonded via a sulfonyl group. Preferred examples include:
methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,
n-butylsulfonyl and tert-butylsulfonyl.
Monoalkylamino in the context of the invention is an amino group
having a linear or branched alkyl substituent having 1 to 4 carbon
atoms. The following may be mentioned by way of example and by way
of preference: methylamino, ethylamino, n-propylamino,
isopropylamino and tert-butylamino.
Dialkylamino in the context of the invention is an amino group
having two identical or different, straight-chain or branched alkyl
substituents each having 1 to 4 carbon atoms. The following may be
mentioned by way of example and by way of preference:
N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino,
N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and
N-tert-butyl-N-methylamino.
Monoalkylaminocarbonyl in the context of the invention is an amino
group which is attached via a carbonyl group and has a
straight-chain or branched alkyl substituent having 1 to 4 carbon
atoms. The following may be mentioned by way of example and by way
of preference: methylaminocarbonyl, ethylaminocarbonyl,
n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl
and tert-butylaminocarbonyl.
Dialkylaminocarbonyl in the context of the invention is an amino
group which is attached via a carbonyl group and has two identical
or different, straight-chain or branched alkyl substituents each
having 1 to 4 carbon atoms. The following may be mentioned by way
of example and by way of preference: N,N-dimethylaminocarbonyl,
N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,
N-methyl-N-n-propylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl
and N-tert-butyl-N-methylaminocarbonyl.
Monoalkylaminocarbonylamino in the context of the invention is an
amino group which carries a straight-chain or branched
alkylaminocarbonyl substituent having 1 to 4 carbon atoms in the
alkyl chain and is attached via the carbonyl group. The following
may be mentioned by way of example and by way of preference:
methylaminocarbonylamino, ethylaminocarbonylamino,
n-propylaminocarbonylamino, isopropylaminocarbonylamino,
n-butylaminocarbonylamino and tert-butylaminocarbonylamino.
Dialkylaminocarbonylamino in the context of the invention is an
amino group which carries a straight-chain or branched
dialkylaminocarbonyl substituent having in each case 1 to 4 carbon
atoms in the alkyl chain which may be identical or different, and
is attached via the carbonyl group. The following may be mentioned
by way of example and by way of preference:
N,N-dimethylaminocarbonylamino, N,N-diethylaminocarbonylamino,
N-ethyl-N-methylaminocarbonylamino,
N-methyl-N-n-propylaminocarbonylamino,
N-n-butyl-N-methylaminocarbonylamino and
N-tert-butyl-N-methylaminocarbonylamino.
Heterocyclyl or heterocyclus in the context of the invention is a
saturated or partially unsaturated heterocycle having a total of 4
to 7 ring atoms which contains 1 to 3 ring heteroatoms from the
group consisting of N, O and S and is attached via a ring carbon
atom or optionally a ring nitrogen atom. Examples include:
azetidinyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl,
dihydroimidazolyl, pyrazolidinyl, dihydrotriazolyl, oxazolidinyl,
dihydrooxazolyl, thiazolidinyl, dihydrooxadiazolyl, piperidinyl,
piperazinyl, tetrahydropyranyl, oxazinanyl, hexahydropyrimidinyl,
morpholinyl, thiomorpholinyl and azepanyl. Preference is given to
5- or 6-membered heterocyclyl radicals having 1 to 3 ring
heteroatoms. The following may be mentioned by way of example and
by way of preference: imidazolidinyl, dihydroimidazolyl,
pyrazolidinyl, dihydrotriazolyl, oxazolidinyl, dihydrooxazolyl,
piperazinyl and morpholinyl.
Heteroaryl in the context of the invention is a monocyclic aromatic
heterocycle (heteroaromatic) which has a total 5 or 6 ring atoms,
contains up to three identical or different ring heteroatoms from
the group of N, O and S and is joined via a ring carbon atom or via
any ring nitrogen atom. Examples include: furyl, pyrrolyl, thienyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preference is
given to monocyclic 5-membered heteroaryl radicals having two or
three ring heteroatoms from the group consisting of N, O and S, for
example thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl,
imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
Halogen in the context of the invention includes fluorine,
chlorine, bromine and iodine. Preference is given to chlorine or
fluorine.
An oxo group in the context of the invention is an oxygen atom
attached to a carbon atom via a double bond.
In the formulae of the group that A, R.sup.1, R.sup.2, R.sup.3 and
R.sup.18 may represent, the end point of the line marked by a
symbol * or ** or *** or # or ## or ### does not represent a carbon
atom or a CH.sub.2 group but is part of the bond to the atom
mentioned in each case.
When radicals in the compounds of the invention are substituted,
the radicals may be mono- or polysubstituted, unless specified
otherwise. In the context of the present invention, all radicals
which occur more than once are defined independently of one
another. Substitution by one or two identical or different
substituents is preferred. Very particular preference is given to
substitution by one substituent.
Preference is given in the context of the present invention to
compounds of the formula (I) in which R.sup.1 represents cyano,
5-membered heterocyclyl or 5-membered heteroaryl, where 5-membered
heterocyclyl may be substituted by oxo, and where 5-membered
heteroaryl may be substituted by hydroxy, or R.sup.1 represents a
group of the formula
##STR00011## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond or
(C.sub.1-C.sub.4)-alkanediyl, R.sup.5 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, R.sup.6 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.4)-alkyl may be
substituted by 1 or 2 substituents independently of one another
selected from the group consisting of fluorine, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy, or
R.sup.5 and R.sup.6 together with the carbon atoms to which they
are attached form a 3- to 6-membered carbocycle, R.sup.7 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyano,
(C.sub.3-C.sub.6)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, or R.sup.1 represents a group of
the formula
##STR00012## where *** represents the point of attachment to the
uracil group, R.sup.2 represents a group of the formula
##STR00013## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, n represents a number 0, 1 or 2, R.sup.10
represents hydrogen, fluorine, chlorine, difluoromethyl,
trifluoromethyl or methyl, R.sup.11A represents hydrogen or
deuterium, R.sup.11B represents hydrogen or deuterium, R.sup.12
represents fluorine, chlorine, methyl or trifluoromethyl, R.sup.13
represents fluorine, chlorine, methyl or trifluoromethyl, R.sup.14
represents hydrogen, R.sup.15 represents hydrogen, R.sup.3
represents
##STR00014## in which # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen, halogen, methoxy or ethoxy, R.sup.18
represents (C.sub.1-C.sub.4)-alkyl, methoxy or ethoxy, or R.sup.18
represents 5- or 6-membered heterocyclyl, where 5- or 6-membered
heterocyclyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
trifluoromethyl, methyl and oxo, R.sup.19 represents hydrogen,
R.sup.20 represents hydrogen, or R.sup.3 represents a group of the
formula
##STR00015## where # represents the point of attachment to the
uracil nitrogen atom, G.sup.1 represents C.dbd.O or SO.sub.2,
G.sup.2 represents CR.sup.27AR.sup.27B, NR.sup.28, O or S, where
R.sup.27A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or
hydroxy, R.sup.27B represents hydrogen, fluorine, chlorine,
(C.sub.1-C.sub.4)-alkyl or trifluoromethyl, or R.sup.27A and
R.sup.27B together with the carbon atom to which they are attached
form a 3- to 6-membered carbocycle, R.sup.28 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, R.sup.25
represents fluorine or methyl, p represents a number 0 or 1,
R.sup.26 represents hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, R.sup.4 represents hydrogen or
methyl, and the salts, solvates and solvates of the salts
thereof.
Preference is given in the context of the present invention to
compounds of the formula (I) in which R.sup.1 represents cyano,
5-membered heterocyclyl or 5-membered heteroaryl, where 5-membered
heterocyclyl may be substituted by oxo, and where 5-membered
heteroaryl may be substituted by hydroxy, or R.sup.1 represents a
group of the formula
##STR00016## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond or
(C.sub.1-C.sub.4)-alkanediyl, R.sup.5 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, R.sup.6 represents hydrogen or
(C.sub.1-C.sub.4)-alkyl, in which (C.sub.1-C.sub.4)-alkyl may be
substituted by 1 or 2 substituents independently of one another
selected from the group consisting of fluorine, trifluoromethyl,
(C.sub.1-C.sub.4)-alkyl, hydroxy and (C.sub.1-C.sub.4)-alkoxy, or
R.sup.5 and R.sup.6 together with the carbon atoms to which they
are attached form a 3- to 6-membered carbocycle, R.sup.7 represents
hydrogen, (C.sub.1-C.sub.4)-alkyl, cyano,
(C.sub.3-C.sub.6)-cycloalkyl, hydroxycarbonyl or
(C.sub.1-C.sub.4)-alkoxycarbonyl, R.sup.2 represents a group of the
formula
##STR00017## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, n represents a number 0, 1 or 2, R.sup.10
represents hydrogen, fluorine, chlorine, difluoromethyl,
trifluoromethyl or methyl, R.sup.11A represents hydrogen or
deuterium, R.sup.11B represents hydrogen or deuterium, R.sup.12
represents fluorine, chlorine, methyl or trifluoromethyl, R.sup.13
represents fluorine, chlorine, methyl or trifluoromethyl, R.sup.14
represents hydrogen, R.sup.15 represents hydrogen, R.sup.3
represents
##STR00018## in which # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen, halogen, methoxy or ethoxy, R.sup.18
represents (C.sub.1-C.sub.4)-alkyl, methoxy or ethoxy, or R.sup.18
represents 5- or 6-membered heterocyclyl, where 5- or 6-membered
heterocyclyl may be substituted by 1 or 2 substituents
independently of one another selected from the group consisting of
trifluoromethyl, methyl and oxo, R.sup.19 represents hydrogen,
R.sup.20 represents hydrogen, or R.sup.3 represents a group of the
formula
##STR00019## where # represents the point of attachment to the
uracil nitrogen atom, G.sup.1 represents C.dbd.O or SO.sub.2,
G.sup.2 represents CR.sup.27AR.sup.27B, NR.sup.28, O or S, where
R.sup.27A represents hydrogen, fluorine, (C.sub.1-C.sub.4)-alkyl or
hydroxy, R.sup.27B represents hydrogen, fluorine, chlorine,
(C.sub.1-C.sub.4)-alkyl or trifluoromethyl, or R.sup.27A and
R.sup.27B together with the carbon atom to which they are attached
form a 3- to 6-membered carbocycle, R.sup.28 represents hydrogen,
(C.sub.1-C.sub.6)-alkyl or (C.sub.3-C.sub.7)-cycloalkyl, R.sup.25
represents fluorine or methyl, p represents a number 0 or 1,
R.sup.26 represents hydrogen, (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.6)-cycloalkyl, R.sup.4 represents hydrogen or
methyl, and the salts, solvates and solvates of the salts
thereof.
Particular preference is given in the context of the present
invention to compounds of the formula (I) in which R.sup.1
represents cyano, or R.sup.1 represents a group of the formula
##STR00020## in which * represents the point of attachment to the
uracil carbon atom, or R.sup.1 represents a group of the
formula
##STR00021## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond,
methanediyl or ethanediyl, R.sup.5 represents hydrogen, R.sup.6
represents hydrogen or methyl, in which methyl may be substituted
by hydroxy, or R.sup.5 and R.sup.6 together with the carbon atom to
which they are attached form a 3- to 5-membered carbocycle, R.sup.7
represents hydrogen, cyano, hydroxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, R.sup.2 represents a group of the formula
##STR00022## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sup.10 represents chlorine or
trifluoromethyl, R.sup.11A represents hydrogen, R.sup.11B
represents hydrogen, R.sup.12 represents chlorine or methyl,
R.sup.13 represents chlorine or trifluoromethyl, R.sup.14
represents hydrogen, R.sup.15 represents hydrogen, R.sup.3
represents
##STR00023## in which # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen or methoxy, R.sup.18 represents methoxy or
ethoxy, or R.sup.18 represents a group of the formula
##STR00024## in which ### represents the point of attachment to the
phenyl ring, R.sup.19 represents hydrogen, R.sup.20 represents
hydrogen, or R.sup.3 represents a group of the formula
##STR00025## where # represents the point of attachment to the
uracil nitrogen atom, R.sup.4 represents hydrogen, and the salts,
solvates and solvates of the salts thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.1 represents cyano,
and the salts, solvates and solvates of the salts thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.1 represents a group
of the formula
##STR00026## in which * represents the point of attachment to the
uracil carbon atom, and the salts, solvates and solvates of the
salts thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.1 represents a group
of the formula
##STR00027## where * represents the point of attachment to the
uracil group, m represents 0 or 1, L.sup.1A represents a bond,
methanediyl or ethanediyl, R.sup.5 represents hydrogen, R.sup.6
represents hydrogen or methyl, in which methyl may be substituted
by hydroxy, or R.sup.5 and R.sup.6 together with the carbon atom to
which they are attached form a 3- to 5-membered carbocycle, R.sup.7
represents hydrogen, cyano, hydroxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, and the salts, solvates and solvates of the salts
thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.2 represents a group
of the formula
##STR00028## where ** represents the point of attachment to the
uracil nitrogen atom, A represents --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, R.sup.10 represents chlorine or
trifluoromethyl, and the salts, solvates and solvates of the salts
thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.3 represents
##STR00029## in which # represents the point of attachment to the
uracil nitrogen atom, R.sup.16 represents hydrogen, R.sup.17
represents hydrogen, R.sup.18 represents methoxy or ethoxy, or
R.sup.18 represents a group of the formula
##STR00030## in which ### represents the point of attachment to the
phenyl ring, R.sup.19 represents hydrogen, R.sup.20 represents
hydrogen, and the salts, solvates and solvates of the salts
thereof.
In the context of the present invention, preference is also given
to compounds of the formula (I) in which R.sup.3 represents a group
of the formula
##STR00031## where # represents the point of attachment to the
uracil nitrogen atom, and the salts, solvates and solvates of the
salts thereof.
Irrespective of the particular combinations of the radicals
specified, the individual radical definitions specified in the
particular combinations or preferred combinations of radicals are
also replaced as desired by radical definitions from other
combinations.
Very particular preference is given to combinations of two or more
of the abovementioned preferred ranges.
The invention further provides a process for preparing compounds of
the formula (I) according to the invention, characterized in that
[A] a compound of the formula (II)
##STR00032## in which T.sup.1A represents (C.sub.1-C.sub.4)-alkyl,
T.sup.2 represents (C.sub.1-C.sub.4)-alkyl, T.sup.3 represents
(C.sub.1-C.sub.4)-alkyl, is reacted in an inert solvent, optionally
in the presence of a suitable base, with a compound of the formula
(III) R.sup.3--NH.sub.2 (III) in which R.sup.3 has the meaning
given above to give a compound of the formula (IV)
##STR00033## in which T.sup.1A and R.sup.3 each have the meanings
given above, this is then reacted in an inert solvent, in the
presence of a suitable base, with a compound of the formula (V)
X.sup.1--R.sup.2 (V) in which R.sup.2 has the meaning given above
and X.sup.1 represents hydroxy or a suitable leaving group, in
particular chlorine, bromine or iodine, to give a compound of the
formula (VI)
##STR00034## in which T.sup.1A, R.sup.2 and R.sup.3 each have the
meanings given above, the compound of the formula (VI) is then
hydrolyzed in an inert solvent in the presence of a suitable acid
or base to give a compound of the formula (VII)
##STR00035## in which T.sup.1B represents hydrogen and in which
R.sup.2 and R.sup.3 each have the meanings given above, and then in
an inert solvent with a compound of the formula (VIII)
##STR00036## converted into a compound of the formula (I-1)
##STR00037## in which R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7,
L.sup.1A and m each have the meanings given above, or [B] a
compound of the formula (IX)
##STR00038## in which T.sup.1A, T.sup.2 and T.sup.3 each have the
meanings mentioned above, is converted in an inert solvent or else
without solvent with a compound of the formula (III) into a
compound of the formula (X)
##STR00039## in which R.sub.3, T.sup.1A and T.sup.3 each have the
meanings given above, this is subsequently reacted in an inert
solvent with chlorosulfonyl isocyanate to give a compound of the
formula (IV) and this is subsequently converted analogously to
process [A] to a compound of the formula (I-1), or [C] a compound
of the formula (XI)
##STR00040## in which T.sup.2 represents (C.sub.1-C.sub.4)-alkyl,
T.sup.3 represents (C.sub.1-C.sub.4)-alkyl and R.sup.4 has the
meaning given above, is reacted in an inert solvent, optionally in
the presence of a suitable base, with a compound of the formula
(III) to give a compound of the formula (XII)
##STR00041## in which R.sup.3 and R.sup.4 each have the meanings
given above, and this is then, by reaction with a compound of the
formula (V) in an inert solvent, if appropriate in the presence of
a suitable base, converted into a compound of the formula (I-2)
##STR00042## in which R.sup.2, R.sup.3 and R.sup.4 each have the
meanings given above, or [D] a compound of the formula (I-2) is
converted with an azide source in the presence of a catalyst in an
inert solvent into a compound of the formula (I-3)
##STR00043## in which R.sup.2, R.sup.3 and R.sup.4 each have the
meanings given above, or [E] a compound of the formula (I-2) is
converted with hydroxylamine into a compound of the formula
(XIII)
##STR00044## in which R.sup.2 and R.sup.3 each have the meanings
given above, and then in an inert solvent with a carbonyl donor or
a thiocarbonyl donor, if appropriate in the presence of a base, to
give a compound of the formula (I-4)
##STR00045## in which R.sup.2 and R.sup.3 each have the meanings
given above and in which Q* represents oxygen or sulfur, any
protecting groups are detached and/or the compounds of the formulae
(I-1), (I-2), (I-3) and (I-4) are, where appropriate, converted
with the appropriate (i) solvents and/or (ii) bases or acids to the
solvates, salts and/or solvates of the salts thereof.
The compounds of the formulae (I-1), (I-2), (I-3) and (I-4) form a
subgroup of the compounds according to the invention of the formula
(I).
Inert solvents for the process steps (II)+(III).fwdarw.(IV),
(IX)+(III).fwdarw.(X) and (XI)+(III).fwdarw.(XII) are, for example,
ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol
dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons
such as benzene, toluene, xylene, hexane, cyclohexane or mineral
oil fractions, halohydrocarbons such as dichloromethane,
1,2-dichloroethane, trichloroethylene or chlorobenzene, alcohols
such as methanol, ethanol, n-propanol, isopropanol or n-butanol, or
other solvents such as dimethylformamide, dimethyl sulfoxide,
N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP),
pyridine, acetone, 2-butanone or acetonitrile. It is also possible
to use mixtures of the solvents mentioned. Preference is given to
using ethanol or acetonitrile.
Suitable bases for the process steps (II)+(III).fwdarw.(IV) und
(XI)+(III).fwdarw.(XII) are alkali metal alkoxides such as sodium
or potassium methoxide, sodium or potassium ethoxide or sodium or
potassium tert-butoxide, alkali metal hydrides such as sodium or
potassium hydride, amides such as sodium amide, lithium or
potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or
organic bases such as triethylamine, diisopropylethylamine,
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or
1,4-diazabicyclo[2.2.2]octane (DABCO.RTM.) or phosphazene bases,
for example
1-[N-tert-butyl-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine
or
N'''-tert-butyl-N,N,N',N'-tetramethyl-N''-[tris(dimethylamino)-lambda.sup-
.5-phosphanylidene]phosphorimidetriamide. Preference is given to
sodium ethoxide, potassium tert-butoxide and triethylamine.
The base is generally used here in an amount of 1 to 5 mol,
preferably in an amount of 1.2 to 3 mol, based on 1 mol of the
compound of the formula (II) or (XI). A base is not required in all
cases.
The conversions (II)+(III).fwdarw.(IV), (IX)+(III).fwdarw.(X) and
(XI)+(III).fwdarw.(XII) are generally carried out within a
temperature range from 0.degree. C. to +200.degree. C., preferably
at +20.degree. C. to +120.degree. C., optionally in a microwave.
The reaction can be carried out under atmospheric, elevated or
reduced pressure (for example from 0.5 to 5 bar). In general, the
reactions are carried out at atmospheric pressure.
If X.sup.1.dbd.OH, the conversions (IV)+(V).fwdarw.(VI) and
(XII)+(V).fwdarw.(I-2) are carried out under Mitsunobu conditions
[see: a) Hughes, D. L. "The Mitsunobu Reaction" Organic Reactions;
John Wiley & Sons, Ltd, 1992, vol. 42, p. 335. b) Hughes, D. L.
Org. Prep. Proceed. Int. 1996, 28, 127]. The Mitsunobu reaction is
effected using triphenylphosphine, or tri-n-butylphosphine,
1,2-bis(diphenylphosphino)ethane (DPPE),
diphenyl(2-pyridyl)phosphine (Ph2P-Py),
(p-dimethylaminophenyl)diphenylphosphine (DAP-DP),
tris(4-dimethylaminophenyl)phosphine (tris-DAP), and a suitable
dialkyl azodicarboxylate, for example diethyl azodicarboxylate
(DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl
azodicarboxylate, N,N,N'N'-tetramethylazodicarboxamide (TMAD),
1,1'-(azodicarbonyl)dipiperidine (ADDP) or
4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD).
Preference is given to using triphenylphosphine and diisopropyl
azodicarboxylate (DIAD).
Inert solvents for the Mitsunobu reactions (IV)+(V).fwdarw.(VI) and
(XII)+(V).fwdarw.(I-2) are, for example, ethers such as
tetrahydrofuran, diethyl ether, hydrocarbons such as benzene,
toluene, xylene, halohydrocarbons such as dichloromethane,
dichloroethane or other solvents such as acetonitrile or
dimethylformamide (DMF). It is also possible to use mixtures of the
solvents mentioned. Preference is given to using THF or a mixture
of THF and DMF.
The Mitsunobu reactions (IV)+(V).fwdarw.(VI) und
(XII)+(V).fwdarw.(I-2) are generally carried out within a
temperature range from -78.degree. C. to +180.degree. C.,
preferably at 0.degree. C. to +50.degree. C., optionally in a
microwave. The conversions can be performed at atmospheric,
elevated or reduced pressure (for example from 0.5 to 5 bar).
If X.sup.1 represents a suitable leaving group, the conversions
(IV)+(V).fwdarw.(VI) and (XII)+(V).fwdarw.(I-2) are carried out
under conditions for a nucleophilic substitution. In that case,
inert solvents for the process steps (IV)+(V).fwdarw.(VI) and
(XII)+(V).fwdarw.(I-2) are, for example, ethers such as diethyl
ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
diethylene glycol dimethyl ether, hydrocarbons such as benzene,
toluene, xylene, hexane, cyclohexane or mineral oil fractions,
halohydrocarbons such as dichloromethane, trichloromethane,
1,2-dichloroethane, trichloroethylene or chlorobenzene, or other
solvents such as dimethylformamide, dimethyl sulfoxide,
N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP),
pyridine, acetone, 2-butanone or acetonitrile. It is also possible
to use mixtures of the solvents mentioned. Preference is given to
using acetonitrile, DMF or acetonitrile in a mixture with
dimethylformamide.
Suitable bases for the process steps (IV)+(V).fwdarw.(VI) and
(XII)+(V).fwdarw.(I-2) are customary inorganic bases. These include
in particular alkali metal or alkaline earth metal carbonates such
as lithium carbonate, sodium carbonate, potassium carbonate,
calcium carbonate or caesium carbonate, optionally with addition of
an alkali metal iodide, for example potassium iodide, alkali metal
alkoxides such as sodium methoxide or potassium methoxide, sodium
ethoxide or potassium ethoxide or sodium tert-butoxide or potassium
tert-butoxide, alkali metal hydrides such as sodium hydride or
potassium hydride, amides such as sodium amide, lithium
bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or
lithium diisopropylamide. Preference is given to using potassium
carbonate with potassium iodide or sodium hydride.
The base is generally used here in an amount of 1 to 5 mol,
preferably in an amount of 1.2 to 3 mol, based on 1 mol of the
compound of the formula (IV) or (XII).
The reactions (IV)+(V).fwdarw.(VI) and (XII)+(V).fwdarw.(I-2) are
generally carried out within a temperature range from 0.degree. C.
to +100.degree. C., preferably at +20.degree. C. to +80.degree. C.,
optionally in a microwave. The reaction can be carried out under
atmospheric, elevated or reduced pressure (for example from 0.5 to
5 bar). In general, the reactions are carried out at atmospheric
pressure.
The hydrolysis of the compounds of the formula (VI) to compounds of
the formula (VII) is effected by treating the esters in inert
solvents with acids or bases, in which latter case the salts formed
at first are converted to the free carboxylic acids by treating
with acid. In general, the ester hydrolysis is preferably effected
with acids.
Suitable inert solvents for these reactions are water, diethyl
ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other
solvents such as acetonitrile, acetic acid, dimethylformamide or
dimethyl sulfoxide. It is also possible to use mixtures of the
solvents mentioned. In the case of a basic ester hydrolysis,
preference is given to using mixtures of water with dioxane,
tetrahydrofuran or acetonitrile. For the hydrolysis of tert-butyl
esters, the solvent used in the case of reaction with
trifluoroacetic acid is preferably dichloromethane, and in the case
of reaction with hydrogen chloride preferably tetrahydrofuran,
diethyl ether or dioxane. For the hydrolysis of other esters under
acidic conditions, preference is given to acetic acid or a mixture
of acetic acid and water.
Suitable bases are the alkali metal or alkaline earth metal
hydrogencarbonates such as sodium or potassium hydrogencarbonate.
Preference is given to sodium hydrogencarbonate.
Suitable acids for the ester cleavage are generally sulfuric acid,
hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic
acid, phosphoric acid, acetic acid, trifluoroacetic acid,
toluenesulfonic acid, methanesulfonic acid or
trifluoromethanesulfonic acid, or mixtures thereof, optionally with
addition of water. Preference is given to hydrogen chloride or
trifluoroacetic acid in the case of the tert-butyl esters, and to
hydrochloric acid in a mixture with acetic acid, and to sulfuric
acid in a mixture with acetic acid and water in the case of the
methyl esters and ethyl esters.
The ester hydrolysis is generally carried out within a temperature
range from 0.degree. C. to 180.degree. C., preferably at
+20.degree. C. to 120.degree. C.
These conversions can be performed at atmospheric, elevated or
reduced pressure (for example from 0.5 to 5 bar). In general, the
reactions are in each case carried out at atmospheric pressure.
Inert solvents for the process step (VII)+(VIII).fwdarw.(I-1) are,
for example, ethers such as diethyl ether, dioxane,
tetrahydrofuran, glycol dimethyl ether or diethylene glycol
dimethyl ether, hydrocarbons such as benzene, toluene, xylene,
hexane, cyclohexane or mineral oil fractions, halohydrocarbons such
as dichloromethane, trichloromethane, tetrachloromethane,
1,2-dichloroethane, trichloroethylene or chlorobenzene, or other
solvents such as acetone, ethyl acetate, acetonitrile, pyridine,
dimethyl sulfoxide, N,N-dimethylformamide,
N,N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It
is likewise possible to use mixtures of the solvents mentioned.
Preference is given to dichloromethane, tetrahydrofuran,
dimethylformamide or mixtures of these solvents.
Suitable condensing agents for the amide formation in process step
(VII)+(VIII).fwdarw.(I-1) are, for example, carbodiimides such as
N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl- and
N,N'-dicyclohexylcarbodiimide (DCC) or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC),
phosgene derivatives such as N,N'-carbonyldiimidazole (CDI),
1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium
3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate,
acylamino compounds such as
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl
chloroformate, propanephosphonic anhydride (T3P),
1-chloro-N,N,2-trimethylprop-1-en-1-amine, diethyl
cyanophosphonate, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate,
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (PyBOP),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TPTU),
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) or
O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TCTU), optionally in combination with further
auxiliaries such as 1-hydroxybenzotriazole (HOBt) or
N-hydroxysuccinimide (HOSu), and also as bases alkali metal
carbonates, for example sodium carbonate or potassium carbonate or
sodium hydrogencarbonate or potassium hydrogencarbonate, or organic
bases such as trialkylamines, e.g. triethylamine,
N-methylmorpholine, N-methylpiperidine or
N,N-diisopropylethylamine. Preference is given to using TBTU in
combination with N-methylmorpholine, HATU in combination with
N,N-diisopropylethylamine or
1-chloro-N,N,2-trimethylprop-1-en-1-amine.
The condensations (VII)+(VIII).fwdarw.(I-1) are generally conducted
within a temperature range from -20.degree. C. to +100.degree. C.,
preferably at 0.degree. C. to +60.degree. C. The conversion can be
carried out under atmospheric, elevated or reduced pressure (for
example from 0.5 to 5 bar). In general, the reactions are carried
out at atmospheric pressure.
Azide sources for the process step (I-2).fwdarw.(I-3) are, for
example, trimethylsilyl azide and sodium azide. Preference is given
to using trimethylsilyl azide. In general, the azide source is, in
particular in the case of trimethylsilyl azide, employed in excess,
for example in an amount of from 1.3 mol to 100 mol, based on 1 mol
of the compound of the formula (I-2).
Inert solvents for the process step (I-2).fwdarw.(I-3) using
trimethylsilyl azide are, for example, ethers such as diethyl
ether, dioxane, tetrahydrofuran, glycol dimethyl ether or
diethylene glycol dimethyl ether, hydrocarbons such as benzene,
toluene, xylene, hexane, cyclohexane or mineral oil fractions, or
other solvents such as chlorobenzene, dimethylformamide, dimethyl
sulfoxide, N,N'-dimethylpropyleneurea (DMPU) or
N-methylpyrrolidinone (NMP). It is also possible to use mixtures of
the solvents mentioned. Preference is given to using toluene. If
sodium azide is used, it may also be suitable to use water,
alcohols such as ethanol, n-butanol, isopropanol or mixtures with
one of the solvents mentioned.
Suitable catalysts for the conversion (I-2).fwdarw.(I-3) when using
trimethylsilyl azide, are organotin oxides, preferably
di-(n-butyl)tin oxide. A suitable catalyst for the conversion
(I-2).fwdarw.(I-3) when using sodium azide is also a Lewis acid
such as zinc bromide, zinc chloride, copper(II) sulfate, aluminum
trichloride or tributyltin chloride. The catalyst is generally used
in an amount of 0.01 to 0.3 mol, preferably in an amount of 0.05 to
0.2 mol, based on 1 mol of the compound of the formula (I-2).
The conversion (I-2).fwdarw.(I-3) is generally carried out within a
temperature range from 20.degree. C. to +180.degree. C., preferably
at +80.degree. C. to +120.degree. C., optionally in a microwave.
The reaction can be carried out under atmospheric, elevated or
reduced pressure (for example from 0.5 to 5 bar). In general, the
reactions are carried out at atmospheric pressure.
Inert solvents for the process step (I-2).fwdarw.(XIII) are, for
example, ethers such as diethyl ether, dioxane, tetrahydrofuran,
glycol dimethyl ether or diethylene glycol dimethyl ether,
hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane
or mineral oil fractions, halohydrocarbons such as dichloromethane,
trichloromethane, 1,2-dichloroethane, trichloroethylene or
chlorobenzene, or other solvents such as dimethylformamide,
dimethyl sulfoxide, N,N'-dimethylpropyleneurea (DMPU),
N-methylpyrrolidinone (NMP) or pyridine. It is also possible to use
mixtures of the solvents mentioned. Preference is given to using
toluene, DMF or DMSO.
The conversion (I-2).fwdarw.(XIII) is generally carried out within
a temperature range from 20.degree. C. to +180.degree. C.,
preferably at +50.degree. C. to +110.degree. C., optionally in a
microwave. The reaction can be carried out under atmospheric,
elevated or reduced pressure (for example from 0.5 to 5 bar). In
general, the reactions are carried out at atmospheric pressure.
Carbonyl donors for the conversion (XIII).fwdarw.(I-4) are, for
example, carbonyldiimidazole, esters of chloroformic acid such as
isobutyl chloroformate or phosgene derivatives such as diphosgene
and triphosgene. Preference is given to using isobutyl
chloroformate. Preferred for use as thiocarbonyl donor is
thiocarbonyldiimidazole.
Inert solvents for the reaction of the compound of the formula
(XIII) with a carbonyl donor or a thiocarbonyl donor are, for
example, ethers such as diethyl ether, dioxane, tetrahydrofuran,
glycol dimethyl ether or diethylene glycol dimethyl ether,
hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane
or mineral oil fractions, halohydrocarbons such as dichloromethane,
trichloromethane, 1,2-dichloroethane, trichloroethylene or
chlorobenzene, or other solvents such as dimethylformamide,
dimethyl sulfoxide, N,N'-dimethylpropyleneurea (DMPU),
N-methylpyrrolidinone (NMP), acetonitrile or pyridine. It is also
possible to use mixtures of the solvents mentioned. Preference is
given to using toluene, THF or DMF.
When using a chlorine-containing carbonyl donor such as isobutyl
chloroformate, it is advantageous to carry out the reaction in the
presence of a suitable base. Suitable bases are, for example,
pyridine and organic bases such as triethylamine,
diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preference is given to
pyridine.
The conversion of the compound of the formula (XIII) with a
carbonyl donor or a thiocarbonyl donor into the corresponding
intermediate is generally carried out in a temperature range of
from 0.degree. C. to 80.degree. C., preferably at RT.
The cyclization of the intermediate from the reaction with a
carbonyl donor to give the oxadiazolone is in most cases carried
out at elevated temperatures, for example from RT to 200.degree.
C., optionally in a microwave. In some cases, it is advantageous to
employ a base such as potassium tert-butoxide or sodium
tert-butoxide.
The cyclization of the intermediate from the reaction with a
thiocarbonyl donor to give the thiadiazolone is carried out using
boron trifluoride/diethyl ether complex. Suitable solvents are
ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol
dimethyl ether or diethylene glycol dimethyl ether. Preference is
given to THF. The conversion is carried out in a temperature range
from 0.degree. C. to 70.degree. C., preferably at RT.
The preparation of the inventive compounds can be illustrated by
way of example by the following synthesis schemes:
##STR00046## ##STR00047##
##STR00048## ##STR00049##
The compounds of the formulae (II), (III), (V), (VIII), (IX) and
(XI) are commercially available or known from the literature, or
can be prepared in analogy to processes known from the
literature.
Further compounds of the invention can optionally also be prepared
by conversions of functional groups of individual substituents,
starting with the compounds of the formula (I) obtained by above
processes. These conversions are performed as described in the
present experimental section, by customary methods known to those
skilled in the art and include, for example, reactions such as
nucleophilic and electrophilic substitutions, oxidations,
reductions, hydrogenations, transition metal-catalysed coupling
reactions, eliminations, alkylation, amination, esterification,
ester hydrolysis, etherification, ether cleavage, formation of
carbonamides, and introduction and removal of temporary protecting
groups.
The compounds of the invention have valuable pharmacological
properties and can be used for treatment and/or prophylaxis of
diseases in humans and animals.
The compounds of the invention are chymase inhibitors and are
therefore suitable for treatment and/or prophylaxis of
cardiovascular, inflammatory, allergic and/or fibrotic
disorders.
In the context of the present invention, disorders of the
cardiovascular system or cardiovascular disorders are understood to
mean, for example, the following disorders: acute and chronic heart
failure, arterial hypertension, coronary heart disease, stable and
unstable angina pectoris, myocardial ischaemia, myocardial
infarction, shock, atherosclerosis, cardiac hypertrophy, cardiac
fibrosis, atrial and ventricular arrhythmias, transitory and
ischaemic attacks, stroke, pre-eclampsia, inflammatory
cardiovascular disorders, peripheral and cardiac vascular
disorders, peripheral perfusion disorders, arterial pulmonary
hypertension, spasms of the coronary arteries and peripheral
arteries, thromboses, thromboembolic disorders, oedema development,
for example pulmonary oedema, cerebral oedema, renal oedema or
heart failure-related oedema, and restenoses such as after
thrombolysis treatments, percutaneous transluminal angioplasty
(PTA), transluminal coronary angioplasty (PTCA), heart transplants
and bypass operations, and micro- and macrovascular damage
(vasculitis), reperfusion damage, arterial and venous thromboses,
microalbuminuria, myocardial insufficiency, endothelial
dysfunction, elevated levels of fibrinogen and of low-density LDL
and elevated concentrations of plasminogen activator/inhibitor 1
(PAI-1).
In the context of the present invention, the term "heart failure"
also includes more specific or related types of disease, such as
acutely decompensated heart failure, right heart failure, left
heart failure, global failure, ischaemic cardiomyopathy, dilated
cardiomyopathy, congenital heart defects, heart valve defects,
heart failure associated with heart valve defects, mitral stenosis,
mitral insufficiency, aortic stenosis, aortic insufficiency,
tricuspid stenosis, tricuspid insufficiency, pulmonary valve
stenosis, pulmonary valve insufficiency, combined heart valve
defects, myocardial inflammation (myocarditis), chronic
myocarditis, acute myocarditis, viral myocarditis, diabetic heart
failure, alcoholic cardiomyopathy, cardiac storage disorders, and
diastolic and systolic heart failure.
The compounds according to the invention are further suitable for
the prophylaxis and/or treatment of polycystic kidney disease
(PCKD) and of the syndrome of inappropriate ADH secretion
(SIADH).
The compounds of the invention are also suitable for treatment
and/or prophylaxis of kidney disorders, in particular of acute and
chronic renal insufficiency and acute and chronic renal
failure.
In the context of the present invention, the term "acute renal
insufficiency" encompasses acute manifestations of kidney disease,
of kidney failure and/or renal insufficiency with and without the
need for dialysis, and also underlying or related renal disorders
such as renal hypoperfusion, intradialytic hypotension, volume
deficiency (e.g. dehydration, blood loss), shock, acute
glomerulonephritis, haemolytic-uraemic syndrome (HUS), vascular
catastrophe (arterial or venous thrombosis or embolism),
cholesterol embolism, acute Bence-Jones kidney in the event of
plasmacytoma, acute supravesicular or subvesicular efflux
obstructions, immunological renal disorders such as kidney
transplant rejection, immune complex-induced renal disorders,
tubular dilatation, hyperphosphataemia and/or acute renal disorders
characterized by the need for dialysis, including in the case of
partial resections of the kidney, dehydration through forced
diuresis, uncontrolled blood pressure rise with malignant
hypertension, urinary tract obstruction and infection and
amyloidosis, and systemic disorders with glomerular factors, such
as rheumatological-immunological systemic disorders, for example
lupus erythematodes, renal artery thrombosis, renal vein
thrombosis, analgesic nephropathy and renal tubular acidosis, and
x-ray contrast agent- and medicament-induced acute interstitial
renal disorders.
In the context of the present invention, the term "chronic renal
insufficiency" encompasses chronic manifestations of kidney
disease, of kidney failure and/or renal insufficiency with and
without the need for dialysis, and also underlying or related renal
disorders such as renal hypoperfusion, intradialytic hypotension,
obstructive uropathy, glomerulopathy, glomerular and tubular
proteinuria, renal oedema, haematuria, primary, secondary and
chronic glomerulonephritis, membranous and membranoproliferative
glomerulonephritis, Alport syndrome, glomerulosclerosis,
tubulointerstitial disorders, nephropathic disorders such as
primary and congenital kidney disease, renal inflammation,
immunological renal disorders such as kidney transplant rejection,
immune complex-induced renal disorders, diabetic and non-diabetic
nephropathy, pyelonephritis, renal cysts, nephrosclerosis,
hypertensive nephrosclerosis and nephrotic syndrome, which can be
characterized diagnostically, for example, by abnormally reduced
creatinine and/or water excretion, abnormally elevated blood
concentrations of urea, nitrogen, potassium and/or creatinine,
altered activity of renal enzymes, for example glutamyl synthetase,
altered urine osmolarity or urine volume, elevated
microalbuminuria, macroalbuminuria, glomerular and arteriolar
lesions, tubular dilatation, hyperphosphataemia and/or the need for
dialysis, and in the event of renal cell carcinoma, after partial
resections of the kidney, dehydration through forced diuresis,
uncontrolled blood pressure rise with malignant hypertension,
urinary tract obstruction and infection and amyloidosis, and
systemic disorders with glomerular factors, such as
rheumatological-immunological systemic disorders, for example lupus
erythematodes, and also renal artery stenosis, renal artery
thrombosis, renal vein thrombosis, analgesic nephropathy and renal
tubular acidosis. In addition, x-ray contrast agent- and
medicament-induced chronic interstitial renal disorders, metabolic
syndrome and dyslipidaemia. The present invention also encompasses
the use of the compounds of the invention for the treatment and/or
prophylaxis of sequelae of renal insufficiency, for example
pulmonary oedema, heart failure, uraemia, anaemia, electrolyte
disorders (for example hyperkalaemia, hyponatraemia) and disorders
in bone and carbohydrate metabolism.
In addition, the compounds according to the invention are also
suitable for treatment and/or prophylaxis of pulmonary arterial
hypertension (PAH) and other forms of pulmonary hypertension (PH),
of chronic obstructive pulmonary disease (COPD), of acute
respiratory distress syndrome (ARDS), of acute lung injury (ALI),
of alpha-1-antitrypsin deficiency (AATD), of pulmonary fibrosis, of
pulmonary emphysema (for example pulmonary emphysema caused by
cigarette smoke), of cystic fibrosis (CF), of acute coronary
syndrome (ACS), heart muscle inflammation (myocarditis) and other
autoimmune cardiac disorders (pericarditis, endocarditis,
valvolitis, aortitis, cardiomyopathy), cardiogenic shock,
aneurysms, sepsis (SIRS), multiple organ failure (MODS, MOF),
inflammation disorders of the kidney, chronic intestinal disorders
(IBD, Crohn's Disease, UC), pancreatitis, peritonitis, rheumatoid
disorders, inflammatory skin disorders and inflammatory eye
disorders.
The compounds according to the invention can furthermore be used
for treatment and/or prophylaxis of asthmatic disorders of varying
severity with intermittent or persistent characteristics
(refractive asthma, bronchial asthma, allergic asthma, intrinsic
asthma, extrinsic asthma, medicament- or dust-induced asthma), of
various forms of bronchitis (chronic bronchitis, infectious
bronchitis, eosinophilic bronchitis), of Bronchiolitis obliterans,
bronchiectasis, pneumonia, idiopathic interstitial pneumonia,
farmer's lung and related disorders, of coughs and colds (chronic
inflammatory cough, iatrogenic cough), inflammation of the nasal
mucosa (including medicament-related rhinitis, vasomotoric rhinitis
and seasonal allergic rhinitis, for example hay fever) and of
polyps.
The compounds according to the invention are also suitable for
treatment and/or prophylaxis of fibrotic disorders of the internal
organs, for example the lung, the heart, the kidney, the bone
marrow and in particular the liver, and also dermatological
fibroses and fibrotic eye disorders. In the context of the present
invention, the term "fibrotic disorders" encompasses particularly
the following terms: hepatic fibrosis, cirrhosis of the liver,
pulmonary fibrosis, endomyocardial fibrosis, cardiomyopathy,
nephropathy, glomerulonephritis, interstitial renal fibrosis,
fibrotic damage resulting from diabetes, bone marrow fibrosis and
similar fibrotic disorders, scleroderma, morphea, keloids,
hypertrophic scarring (also following surgical procedures), naevi,
diabetic retinopathy and proliferative vitroretinopathy.
The compounds according to the invention are also suitable for
controlling postoperative scarring, for example as a result of
glaucoma operations.
Furthermore, the compounds according to the invention can also be
used cosmetically for ageing and keratinized skin.
In addition, the compounds of the invention can also be used for
treatment and/or prophylaxis of dyslipidaemias
(hypercholesterolaemia, hypertriglyceridaemia, elevated
concentrations of the postprandial plasma triglycerides,
hypoalphalipoproteinaemia, combined hyperlipidaemias), nephropathy
and neuropathy), cancers (skin cancer, brain tumours, breast
cancer, bone marrow tumours, leukaemias, liposarcomas, carcinoma of
the gastrointestinal tract, of the liver, pancreas, lung, kidney,
urinary tract, prostate and genital tract, and also malignant
tumours in the lymphoproliferative system, for example Hodgkin's
and non-Hodgkin's lymphoma), of disorders of the gastrointestinal
tract and of the abdomen (glossitis, gingivitis, periodontitis,
oesophagitis, eosinophilic gastroenteritis, mastocytosis, Crohn's
disease, colitis, proctitis, pruritus ani, diarrhoea, coeliac
disease, hepatitis, chronic hepatitis, hepatic fibrosis, cirrhosis
of the liver, pancreatitis and cholecystitis), skin disorders
(allergic skin disorders, psoriasis, acne, eczema, neurodermitis,
various forms of dermatitis, and also keratitis, bullosis,
vasculitis, cellulitis, panniculitis, lupus erythematodes,
erythema, lymphoma, skin cancer, Sweet's syndrome, Weber-Christian
syndrome, scarring, warts, chillblains), of disorders of the
skeletal bone and of the joints, and also of the skeletal muscle
(various forms of arthritis, various forms of arthropathies,
scleroderma and of further disorders with an inflammatory or
immunological component, for example paraneoplastic syndrome, in
the event of rejection reactions after organ transplants and for
wound healing and angiogenesis, especially in the case of chronic
wounds.
The compounds of the formula (I) according to the invention are
additionally suitable for treatment and/or prophylaxis of
ophthalmologic disorders, for example glaucoma, normotensive
glaucoma, high intraocular pressure and combinations thereof, of
age-related macular degeneration (AMD), of dry or non-exudative
AMD, moist or exudative or neovascular AMD, choroidal
neovascularization (CNV), detached retina, diabetic retinopathy,
atrophic lesions to the retinal pigment epithelium (RPE),
hypertrophic lesions to the retinal pigment epithelium (RPE),
diabetic macular oedema, retinal vein occlusion, choroidal retinal
vein occlusion, macular oedema, macular oedema due to retinal vein
occlusion, angiogenesis at the front of the eye, for example
corneal angiogenesis, for example following keratitis, cornea
transplant or keratoplasty, corneal angiogenesis due to hypoxia
(extensive wearing of contact lenses), pterygium conjunctiva,
subretinal oedema and intraretinal oedema.
In addition, the compounds of the formula (I) according to the
invention are suitable for the treatment and/or prophylaxis of
elevated and high intraocular pressure resulting from traumatic
hyphaema, periorbital oedema, postoperative viscoelastic retention,
intraocular inflammation, use of corticosteroids, pupillary block
or idiopathic causes, and of elevated intraocular pressure
following trabeculectomy and due to pre-operative conditions.
The present invention further provides for the use of the compounds
according to the invention for treatment and/or prophylaxis of
disorders, especially the disorders mentioned above.
The present invention further provides for the use of the compounds
according to the invention for production of a medicament for
treatment and/or prophylaxis of disorders, especially the disorders
mentioned above.
The present invention further provides the compounds according to
the invention for use in a method for treatment and/or prophylaxis
of heart failure, pulmonary hypertension, chronic obstructive
pulmonary disease, asthma, kidney failure, nephropathy, fibrotic
disorders of the internal organs and dermatological fibroses.
The compounds of the invention can be used alone or, if required,
in combination with other active ingredients. Accordingly, the
present invention further provides medicaments comprising at least
one of the compounds according to the invention and one or more
further active compounds, especially for treatment and/or
prophylaxis of the aforementioned disorders. Preferred examples of
active compounds suitable for combinations include:
compounds which inhibit the signal transduction cascade, by way of
example and with preference from the group of the kinase
inhibitors, especially from the group of the tyrosine kinase and/or
serine/threonine kinase inhibitors;
compounds which inhibit the degradation and alteration of the
extracellular matrix, by way of example and with preference
inhibitors of the matrix metalloproteases (MMPs), especially
inhibitors of stromelysin, collagenases, gelatinases and
aggrecanases (in this context particularly of MMP-1, MMP-3, MMP-8,
MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase (MMP-12);
compounds which block the binding of serotonin to its receptors, by
way of example and with preference antagonists of the 5-HT.sub.2b
receptor; organic nitrates and NO donors, for example sodium
nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide
dinitrate, molsidomine or SIN-1, and inhaled NO; NO-independent but
haem-dependent stimulators of soluble guanylate cyclase, such as
especially the compounds described in WO 00/06568, WO 00/06569, WO
02/42301 and WO 03/095451; NO- and haem-independent activators of
soluble guanylate cyclase, such as especially the compounds
described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO
02/070462 and WO 02/070510; prostacyclin analogues, by way of
example and with preference iloprost, beraprost, treprostinil or
epoprostenol; compounds which inhibit soluble epoxide hydrolase
(sEH), for example N,N'-dicyclohexylurea,
12-(3-adamantan-1-ylureido)dodecanoic acid or
1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea;
compounds which influence the energy metabolism of the heart, by
way of example and with preference etomoxir, dichloroacetate,
ranolazine or trimetazidine; compounds which inhibit the
degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic
adenosine monophosphate (cAMP), for example inhibitors of
phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5
inhibitors such as sildenafil, vardenafil and tadalafil;
antithrombotic agents, by way of example and with preference from
the group of the platelet aggregation inhibitors, the
anticoagulants or the profibrinolytic substances; hypotensive
active ingredients, for example and with preference from the group
of calcium antagonists, angiotensin AII antagonists, ACE
inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin
inhibitors, alpha-receptor blockers, beta-receptor blockers,
mineralocorticoid receptor antagonists, and rho kinase inhibitors
and the diuretics; vasopressin receptor antagonists, for example
and with preference conivaptan, tolvaptan, lixivaptan, mozavaptan,
satavaptan, SR-121463, RWJ 676070 or BAY 86-8050; bronchodilatory
agents, by way of example and with preference from the group of the
beta-adrenergic receptor agonists, such as especially albuterol,
isoproterenol, metaproterenol, terbutalin, formoterol or
salmeterol, or from the group of the anticholinergics, such as
especially ipratropium bromide; anti-inflammatory agents, by way of
example and with preference from the group of the glucocorticoids,
such as especially prednisone, prednisolone, methylprednisolone,
triamcinolone, dexamethasone, beclomethasone, betamethasone,
flunisolide, budesonide or fluticasone; and/or active compounds
altering lipid metabolism, for example and with preference from the
group of the thyroid receptor agonists, cholesterol synthesis
inhibitors such as, by way of example and preferably, HMG-CoA
reductase inhibitors or squalene synthesis inhibitors, the ACAT
inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma
and/or PPAR-delta agonists, cholesterol absorption inhibitors,
lipase inhibitors, polymeric bile acid adsorbents, bile acid
reabsorption inhibitors and lipoprotein(a) antagonists.
In a preferred embodiment of the invention, the compounds according
to the invention are used in combination with a kinase inhibitor,
by way of example and with preference bortezomib, canertinib,
erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib,
lonafarnib, pegaptinib, pelitinib, semaxanib, sorafenib,
regorafenib, sunitinib, tandutinib, tipifarnib, vatalanib, fasudil,
lonidamine, leflunomide, BMS-3354825 or Y-27632.
In a preferred embodiment of the invention, the compounds according
to the invention are used in combination with a serotonin receptor
antagonist, by way of example and with preference PRX-08066.
Antithrombotic agents are preferably understood to mean compounds
from the group of the platelet aggregation inhibitors, the
anticoagulants or the profibrinolytic substances.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a platelet
aggregation inhibitor, by way of example and with preference
aspirin, clopidogrel, ticlopidine or dipyridamole.
In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a thrombin
inhibitor, by way of example and with preference ximelagatran,
melagatran, bivalirudin or clexane.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a GPIIb/IIIa
antagonist, by way of example and with preference tirofiban or
abciximab.
In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a factor Xa
inhibitor, by way of example and with preference rivaroxaban,
DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112,
YM-150, KFA-1982, EMD-503982, MCM-17, mLN-1021, DX 9065a, DPC 906,
JTV 803, SSR-126512 or SSR-128428.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with heparin or with a
low molecular weight (LMW) heparin derivative.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a vitamin K
antagonist, by way of example and with preference coumarin.
Hypotensive agents are preferably understood to mean compounds from
the group of calcium antagonists, angiotensin AII antagonists, ACE
inhibitors, endothelin antagonists, renin inhibitors,
alpha-receptor blockers, beta-receptor blockers, mineralocorticoid
receptor antagonists, rho kinase inhibitors, and the diuretics.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a calcium
antagonist, by way of example and with preference nifedipine,
amlodipine, verapamil or diltiazem.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an alpha-1-receptor
blocker, by way of example and with preference prazosin.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a beta-receptor
blocker, by way of example and with preference propranolol,
atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol,
bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol,
metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol,
labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or
bucindolol.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an angiotensin AII
antagonist, by way of example and with preference losartan,
candesartan, valsartan, telmisartan or embursatan.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an ACE inhibitor, by
way of example and with preference enalapril, captopril,
lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril
or trandopril.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an endothelin
antagonist, by way of example and with preference bosentan,
darusentan, ambrisentan or sitaxsentan.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a renin inhibitor,
by way of example and with preference aliskiren, SPP-600 or
SPP-800.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a mineralocorticoid
receptor antagonist, by way of example and with preference
spironolactone or eplerenone.
In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a rho kinase
inhibitor, by way of example and with preference fasudil, Y-27632,
SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077,
GSK-269962A or BA-1049.
In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a diuretic,
by way of example and with preference furosemide.
Lipid metabolism modifiers are preferably understood to mean
compounds from the group of the CETP inhibitors, thyroid receptor
agonists, cholesterol synthesis inhibitors such as HMG-CoA
reductase inhibitors or squalene synthesis inhibitors, the ACAT
inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or
PPAR-delta agonists, cholesterol absorption inhibitors, polymeric
bile acid adsorbents, bile acid reabsorption inhibitors, lipase
inhibitors and the lipoprotein(a) antagonists.
In a preferred embodiment of the invention, the compounds according
to the invention are administered in combination with a CETP
inhibitor, by way of example and with preference torcetrapib
(CP-529 414), JJT-705 or CETP vaccine (Avant).
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a thyroid receptor
agonist such as, for example and preferably, D-thyroxine,
3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS
26214).
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an HMG-CoA reductase
inhibitor from the class of statins, by way of example and with
preference lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin, rosuvastatin or pitavastatin.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a squalene synthesis
inhibitor, by way of example and with preference BMS-188494 or
TAK-475.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an ACAT inhibitor,
by way of example and with preference avasimibe, melinamide,
pactimibe, eflucimibe or SMP-797.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with an MTP inhibitor, by
way of example and with preference implitapide, BMS-201038,
R-103757 or JTT-130.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a PPAR-gamma
agonist, by way of example and with preference pioglitazone or
rosiglitazone.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a PPAR-delta
agonist, by way of example and with preference GW 501516 or BAY
68-5042.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a cholesterol
absorption inhibitor, by way of example and with preference
ezetimibe, tiqueside or pamaqueside.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a lipase inhibitor,
by way of example and with preference orlistat.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a polymeric bile
acid adsorbent, by way of example and with preference
cholestyramine, colestipol, colesolvam, CholestaGel or
colestimide.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a bile acid
reabsorption inhibitor, by way of example and with preference ASBT
(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105,
BARI-1741, SC-435 or SC-635.
In a preferred embodiment of the invention, the compounds of the
invention are administered in combination with a lipoprotein(a)
antagonist, by way of example and with preference gemcabene calcium
(CI-1027) or nicotinic acid.
The present invention further provides medicaments which comprise
at least one compound of the invention, typically together with one
or more inert, nontoxic, pharmaceutically suitable excipients, and
for the use thereof for the aforementioned purposes.
The compounds of the invention can act systemically and/or locally.
For this purpose, they can be administered in a suitable manner,
for example by the oral, parenteral, pulmonal, nasal, sublingual,
lingual, buccal, rectal, dermal, transdermal, conjunctival or otic
route, or as an implant or stent.
The compounds of the invention can be administered in
administration forms suitable for these administration routes.
Suitable administration forms for oral administration are those
which work according to the prior art and release the compounds of
the invention rapidly and/or in a modified manner and which contain
the compounds of the invention in crystalline and/or amorphized
and/or dissolved form, for example tablets (uncoated or coated
tablets, for example with gastric juice-resistant or
retarded-dissolution or insoluble coatings which control the
release of the compound of the invention), tablets or films/oblates
which disintegrate rapidly in the oral cavity, films/lyophilizates,
capsules (for example hard or soft gelatin capsules), sugar-coated
tablets, granules, pellets, powders, emulsions, suspensions,
aerosols or solutions.
Parenteral administration can bypass an absorption step (e.g.
intravenously, intraarterially, intracardially, intraspinally or
intralumbally) or include an absorption (e.g. inhalatively,
intramuscularly, subcutaneously, intracutaneously, percutaneously
or intraperitoneally). Administration forms suitable for parenteral
administration include preparations for injection and infusion in
the form of solutions, suspensions, emulsions, lyophilizates or
sterile powders.
For the other administration routes, suitable examples are
inhalation medicaments (including powder inhalers, nebulizers,
aerosols), nasal drops, solutions or sprays; tablets for lingual,
sublingual or buccal administration, films/oblates or capsules,
suppositories, ear or eye preparations, vaginal capsules, aqueous
suspensions (lotions, shaking mixtures), lipophilic suspensions,
ointments, creams, transdermal therapeutic systems (e.g. patches),
milk, pastes, foams, dusting powders, implants or stents.
Oral and parenteral administration are preferred, especially oral,
intravenous and inhalative administration.
The compounds of the invention can be converted to the
administration forms mentioned. This can be done in a manner known
per se, by mixing with inert, nontoxic, pharmaceutically suitable
excipients. These excipients include carriers (for example
microcrystalline cellulose, lactose, mannitol), solvents (e.g.
liquid polyethylene glycols), emulsifiers and dispersing or wetting
agents (for example sodium dodecylsulfate, polyoxysorbitan oleate),
binders (for example polyvinylpyrrolidone), synthetic and natural
polymers (for example albumin), stabilizers (e.g. antioxidants, for
example ascorbic acid), colorants (e.g. inorganic pigments, for
example iron oxides) and flavour and/or odour correctants.
In general, it has been found to be advantageous in the case of
parenteral administration to administer amounts of about 0.001 to 1
mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to
achieve effective results. In the case of oral administration the
dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20
mg/kg and most preferably 0.1 to 10 mg/kg of body weight.
It may nevertheless be necessary in some cases to deviate from the
stated amounts, specifically as a function of the body weight,
route of administration, individual response to the active
ingredient, nature of the preparation and time or interval over
which administration takes place. Thus, in some cases less than the
abovementioned minimum amount may be sufficient, while in other
cases the upper limit mentioned must be exceeded. In the case of
administration of greater amounts, it may be advisable to divide
them into several individual doses over the day.
The working examples which follow illustrate the invention. The
invention is not restricted to the examples.
Unless stated otherwise, the percentages in the tests and examples
which follow are percentages by weight; parts are parts by weight.
Solvent ratios, dilution ratios and concentration data for
liquid/liquid solutions, unless indicated otherwise, are based in
each case on volume.
A. EXAMPLES
Abbreviations
Ac acetyl aq. aqueous, aqueous solution br.d broad doublet (NMR)
br.m broad multiplet (NMR) br.s broad singlet (NMR) br.t broad
triplet (NMR) Ex. Example c concentration cat. catalytic TLC
thin-layer chromatography DCI direct chemical ionization (in MS)
DCC dicyclohexylcarbodiimide DIAD diisopropyl azodicarboxylate DIEA
N,N-diisopropylethylamine DMAP 4-N,N-dimethylaminopyridine DMF
dimethylformamide DMSO dimethyl sulfoxide EDC
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride ee
enantiomeric excess eq. equivalent(s) ESI electrospray ionization
(in MS) Et ethyl GC-MS gas chromatography-coupled mass spectrometry
h hour(s) HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate HOBt 1-hydroxy-1H-benzotriazole hydrate HPLC
high-pressure, high-performance liquid chromatography conc.
concentrated LC-MS liquid chromatography-coupled mass spectrometry
Me methyl min minute(s) MS mass spectrometry MTBE methyl tert-butyl
ether NMR nuclear magnetic resonance spectrometry Pd/C palladium on
activated carbon Ph phenyl PyBOP
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate quant. quantitative (in yield) quin quintet
(NMR) rac racemic, racemate RT room temperature R.sub.t retention
time (in HPLC) tBu tert-butyl TBTU
(benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate tert
tertiary TFA trifluoroacetic acid TFAA trifluoroacetic anhydride
THF tetrahydrofuran TPPO triphenylphosphine oxide UV ultraviolet
spectrometry v/v volume to volume ratio (of a solution) HPLC, GC-MS
and LC-MS Methods:
Method 1 (LC-MS): Instrument: Waters ACQUITY SQD UPLC system;
column: Waters Acquity UPLC HSS T3 1.8.mu. 50.times.1 mm; mobile
phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile
phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid;
gradient: 0.0 min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A;
oven: 50.degree. C.; flow rate: 0.40 ml/min; UV detection: 210-400
nm.
Method 2 (LC-MS) instrument: Micromass Quattro Premier with Waters
UPLC Acquity; column: Thermo Hypersil GOLD 1.9.mu. 50.times.1 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 90% A.fwdarw.0.1 min 90% A.fwdarw.1.5 min
10% A.fwdarw.2.2 min 10% A oven: 50.degree. C.; flow rate: 0.33
ml/min; UV detection: 210 nm.
Method 3 (LC-MS): Instrument: Micromass Quattro Premier with Waters
UPLC Acquity; column: Thermo Hypersil GOLD 1.9.mu. 50.times.1 mm;
mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid,
mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic
acid; gradient: 0.0 min 97% A.fwdarw.0.5 min 97% A.fwdarw.3.2 min
5% A.fwdarw.4.0 min 5% A oven: 50.degree. C.; flow rate: 0.3
ml/min; UV detection: 210 nm.
Method 4 (LC-MS): MS instrument type: Waters (Micromass) Quattro
Micro; HPLC instrument type: Agilent 1100 series; column: Thermo
Hypersil GOLD 3.mu. 20.times.4 mm; mobile phase A: 1 l of water+0.5
ml of 50% strength formic acid, mobile phase B: 1 l of
acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min
100% A.fwdarw.3.0 min 10% A.fwdarw.4.0 min 10% A; oven: 50.degree.
C.; flow rate: 2 ml/min; UV detection: 210 nm.
Method 5 (preparative HPLC): Column: Reprosil C18, 10 .mu.m, 250
mm.times.30 mm. Mobile phase A: formic acid 0.1% in water, mobile
phase B: acetonitrile; flow rate: 50 ml/min; gradient: 0 to 6 min:
90% A/10% B; 6 min to 27 min: gradient to 95% B; 27 min to 38 min
95% B; 38 min to 39 min gradient to 10% B; 39 min to 43 min (end):
60% A/40% B. Slight variations in the gradient are possible.
Method 6 (preparative HPLC): As Method 4, but using the Chromatorex
C18 5 .mu.m, 250.times.20 mm column.
Method 7 (preparative HPLC): Column: Reprosil C18 10 .mu.m,
250.times.30, flow rate 50 ml/min, detection at 210 nm, mobile
phase acetonitrile (A), water (B); gradient: 3 min 10% A, 27 min
95% A, 34 min 95% A, 34-38 min 10% A.
Method 8 (preparative HPLC): Column: Reprosil C18, 10 .mu.m, 250
mm.times.30 mm. Mobile phase A: formic acid 0.1% in water, mobile
phase B: methanol; flow rate: 50 ml/min; programme: 0 to 4.25 min:
60% A/40% B; 4.25 to 4.50 min: gradient to 60% B; 4.50 min to 17
min gradient to 100% B; 17 min to 19.50 min 100% B; 19.50 min to
19.75 min gradient to 40% B; 19.75 min to 22 min (end): 60% A/40%
B. Slight variations in the gradient are possible.
Method 9 (preparative HPLC): Column: Reprosil C18, 10 .mu.m, 250
mm.times.30 mm. Mobile phase A: water, mobile phase B: methanol;
flow rate: 50 ml/min; programme: 0 to 4.25 min: 50% A/50% B; 4.25
to 4.50 min: gradient to 70% B; 4.50 min to 11.5 min gradient to
90% B; 12.00 min to 14.50 min 100% B; 14.50 min to 18.00 min
gradient to 50% B (end): Slight variations in the gradient are
possible.
Method 10 (preparative HPLC): Column: Reprosil C18, 10 .mu.m, 250
mm.times.30 mm. Mobile phase A: water, mobile phase B: methanol;
flow rate: 50 ml/min; programme: 0 to 4.25 min: 70% A/30% B; 4.25
to 4.50 min: gradient to 50% B; 4.50 min to 11.5 min gradient to
70% B; 12.00 min to 14.50 min 100% B; 14.50 min to 18.00 min
gradient to 30% B (end): Slight variations in the gradient are
possible.
Method 11 (preparative HPLC): Column: Reprosil C18, 10 .mu.m, 250
mm.times.30 mm. Mobile phase A: water, mobile phase B: methanol;
flow rate: 50 ml/min; programme: 0 to 4.25 min: 60% A/40% B; 4.25
to 4.50 min: gradient to 60% B; 4.50 min to 17 min gradient to 100%
B; 17 min to 19.50 min 100% B; 19.50 min to 19.75 min gradient to
40% B; 19.75 min to 22 min (end): 60% A/40% B.
Method 12 (MS; DCI NH.sub.3): Instrument: Thermo Fisher-Scientific
DSQ; chemical ionization; reactant gas NH.sub.3; source
temperature: 200.degree. C.; ionization energy 70 eV.
Method 13: Instrument: Waters ACQUITY SQD UPLC system; column:
Waters Acquity UPLC HSS T3 1.8.mu. 30.times.2 mm; mobile phase A: 1
l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l
of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0
min 90% A.fwdarw.1.2 min 5% A.fwdarw.2.0 min 5% A; oven: 50.degree.
C.; flow rate: 0.60 ml/min; UV detection: 208-400 nm.
Method 14 (chiral preparative HPLC): Column: Daicel Chiralpak OD-H
5 .mu.m, 250 mm.times.20 mm; mobile phase: 0.2% glacial acetic acid
in acetonitrile/0.2% glacial acetic acid in ethanol 70:30 (v/v).
flow rate 20 ml/min. UV detection: 210 nM, RT.
Method 15 (chiral analytical HPLC): Column: Daicel Chiralpak AD-H 5
.mu.m, 250 mm.times.4.6 mm; mobile phase: 0.2% glacial acetic acid
in acetonitrile/0.2% glacial acetic acid in ethanol 30:70 (v/v).
flow rate 1 ml/min. UV detection: 230 nM, RT.
Method 16 (chiral preparative HPLC): Column: Daicel Chiralpak AD-H
5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol/trifluoroacetic acid/water 49.4:49.4:0.2:1
(v/v/v/v). flow rate 20 ml/min. UV detection: 220 nM, 25.degree.
C.
Method 17 (chiral analytical HPLC): Column: Daicel Chiralpak AD-H 5
.mu.m, 250 mm.times.4.6 mm; mobile phase:
isohexane/ethanol/trifluoroacetic acid/water 49.4:49.4:0.2:1
(v/v/v/v). flow rate 20 ml/min. UV detection: 220 nM, 30.degree.
C.
Method 18 (chiral preparative HPLC): Column: Daicel Chiralpak AD-H
5 .mu.m, 250 mm.times.20 mm; mobile phase:
isohexane/ethanol/trifluoroacetic acid/water 29.6:69.2:0.2:1
(v/v/v/v). flow rate 20 ml/min. UV detection: 210 nM, 25.degree.
C.
Method 19 (LC-MS): MS instrument: Waters (Micromass) QM; HPLC
instrument: Agilent 1100 series; column: Agilent ZORBAX Extend-C18
3.0.times.50 mm 3.5 micron; mobile phase A: 1 l of water+0.01 mol
of ammonium carbonate, mobile phase B: 1 l of acetonitrile;
gradient: 0.0 min 98% A.fwdarw.0.2 min 98% A.fwdarw.3.0 min 5%
A.fwdarw.4.5 min 5% A; oven: 40.degree. C.; flow rate: 1.75 ml/min;
UV detection: 210 nm.
Method 20 (preparative HPLC): Column: Chromatorex C18, 10 .mu.m,
250 mm.times.30 mm. Mobile phase A: water, mobile phase B:
methanol; flow rate: 75 ml/min; programme: 0 to 4.25 min: 60% A/40%
B; 4.25 to 4.50 min: gradient to 60% B; 4.50 min to 9.99 min:
gradient to 80% B; 9.99 to 12.40 min: gradient to 100% B; 12.40 to
17.21 min: 100% B; 17.21 to 17.46 min: gradient to 40% B; 17.46 to
18.22 min (end): 60% A/40% B.
Starting Materials and Intermediates
Example 1A
1,3,3-Trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one
##STR00050##
2.44 g (13.96 mmol) of 1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one
[preparation see: Journal of Organic Chemistry, 2000, vol. 65, 24,
p. 8317-8325] were initially charged in 12 ml of acetic acid, 0.96
ml (13.96 mmol) of nitric acid (65%) was then added dropwise at RT
and the reaction mixture was stirred at RT for 2 weeks. The
reaction mixture was added to ice-water, and the solid formed was
filtered off with suction, washed with water and dried at
50.degree. C. under reduced pressure. This gave 2.32 g (72% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.89 min; MS (ESIpos): m/z=221
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.35 (s, 6H),
3.22 (s, 3H), 7.25 (d, 1H), 8.26 (dd, 1H), 8.33 (d, 1H).
Example 2A
5-Amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one
##STR00051##
2.32 g (10.56 mmol) of
1,3,3-trimethyl-5-nitro-1,3-dihydro-2H-indol-2-one from Example 1A
were initially charged in 71.5 ml of ethanol, 330 mg (0.32 mmol) of
palladium (10% on activated carbon) were added and the mixture was
hydrogenated at hydrogen standard pressure for 2 days.
Subsequently, the reaction mixture was filtered through kieselguhr,
the residue was washed with ethanol and the filtrate was
concentrated. The residue was stirred with a little ethanol,
filtered off, washed with a little ethanol, filtered off with
suction and dried. This gave 1.95 g (93% of theory) of the title
compound.
LC-MS (Method 4): R.sub.t=0.76 min; MS (ESIpos): m/z=191
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.20 (s, 6H),
3.04 (s, 3H), 4.70-4.80 (m, 2H), 6.46 (dd, 1H), 6.58 (d, 1H), 6.67
(d, 1H).
Example 3A
Ethyl
2,4-dioxo-1-[4-(2-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate
##STR00052##
15.96 g (61.6 mmol) of ethyl
3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for preparation
see: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical &
Pharmaceutical Bulletin (1972), 20(7), 1380-8) and 12.0 g (67.7
mmol) of 1-(4-aminophenyl)imidazolidin-2-one (for preparation see:
P. Stabile et al., Tetrahedron Letters 2010, 51 (24), 3232-3235) in
724 ml of ethanol were heated at reflux with stirring for two
hours. The mixture was allowed to cool to 20.degree. C., 6.91 g
(61.6 mmol) of potassium tert-butoxide were added and the mixture
was stirred at 20.degree. C. for a further 18 hours. 1000 ml of
water were added and the mixture was acidified to pH 3 with 1N
aqueous hydrochloric acid. The solid formed was filtered off,
washed with water (200 ml), ethyl acetate (100 ml) and diethyl
ether (100 ml) and dried under high vacuum. This gave 13.54 g (54%
of theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.62 min; m/z=345 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.21 (t, 3H), 3.44 (m,
2H), 3.88 (m, 2H), 4.19 (q, 2H), 7.10 (s, 1H), 7.40 (d, 2H), 7.65
(d, 2H), 8.23 (s, 1H), 11.65 (br. s, 1H).
Example 4A
Ethyl
2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate
##STR00053##
3.02 g (17 mmol) of 3-(4-aminophenyl)-1,3-oxazolidin-2-one
(preparation: see WO2010/019903, p. 222, Method 38; or Farmaco Sci.
Ed. (1969), 179) and 4.0 g (15.4 mmol) of ethyl
3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for preparation
see: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical &
Pharmaceutical Bulletin (1972), 20(7), 1380-8) in 170 ml of ethanol
were heated at reflux for 2 h. After cooling to RT, 1.73 g (15.4
mmol) of potassium tert-butoxide were added and the mixture was
stirred first at RT overnight and then at 50.degree. C. for 5 h.
The reaction mixture was poured into 1.4 l of 1N aqueous
hydrochloric acid and the solid formed was isolated by filtration.
The solid was stirred with diethyl ether and then dried under high
vacuum. This gave 4.2 g (66% of theory, purity 92%) of the title
compound.
LC-MS (Method 1): R.sub.t=0.59 min; m/z=346 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.22 (t, 3H),
4.06-4.14 (m, 2H), 4.17 (q, 2H), 4.43-4.51 (m, 2H), 7.51 (d, 2H),
7.68 (d, 2H), 8.26 (s, 1H), 11.69 (s, 1H).
Example 5A
Ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carboxylate
##STR00054##
40.0 g (243.7 mmol) of 6-amino-3-methyl-1,3-benzoxazol-2(3H)-one
were initially charged in 2.5 l of ethanol, and 63.2 g (243.7 mmol)
ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate (for
preparation see: Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji,
Chemical & Pharmaceutical Bulletin (1972), 20(7), 1380-8) were
added. After a few minutes, a thick suspension formed. This mixture
was heated at reflux temperature for 1.5 h. After cooling to about
60.degree. C., 27.3 g (243.7 mmol) of potassium tert-butoxide were
added and the reaction mixture was stirred further at reflux
temperature for 4.5 h. The mixture was cooled to about 60 C and
then stirred into 10 l of cooled 1N aqueous hydrochloric acid. The
solid was filtered off with suction, washed with water and dried in
a vacuum drying cabinet at 70.degree. C. overnight. This gave 64.0
g (79% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.59 min; MS (ESIpos): m/z=332
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (t, 3H),
3.38 (s, 3H), 4.17 (q, 2H), 7.38 (s, 2H), 7.59 (s, 1H), 8.26 (s,
1H), 11.69 (s, 1H).
Example 6A
Ethyl
1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxy-
late
##STR00055##
5.00 g (17.0 mmol) of diethyl
{[(4-methoxyphenyl)amino]methylene}malonate (prepared according to
Bioorg. Med. Chem. Lett., 16(4) 1010-1013; 2006) and 2.65 g (18.8
mmol) of chlorosulfonyl isocyanate in 30 ml of toluene were stirred
in a microwave apparatus (CEM Discover, initial irradiation power
200 W, target temperature 120.degree. C.) for 45 min. After
concentration, the crude mixture was separated by chromatography on
silica gel using dichloromethane/methanol mixtures with increasing
methanol content (50:1-30:1-10:1). This gave, after concentration
and drying of the appropriate fractions under reduced pressure,
1.14 g (23% of theory) of the target compound.
LC-MS (Method 2): R.sub.t=0.86 min; m/z=291 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.22 (t, 3H), 3.80 (s,
3H), 4.17 (q, 2H), 7.01-7.07 (m, 2H), 7.38-7.44 (m, 2H), 8.22 (s,
1H), 11.63 (br. s, 1H).
Example 7A
Ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3-
,4-tetrahydropyrimidine-5-carboxylate
##STR00056##
450 mg (2.50 mmol) of 6-amino-3-methyl-1,3-benzothiazol-2(3H)-one
(J. Het. Chem. 1992, 29 (5), 1069-1076, Example 8b) and 647 mg
(2.50 mmol) of ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate
were initially charged in 19 ml of ethanol and the mixture was
heated to reflux for 2 h. After cooling to RT, 280 mg (2.50 mmol)
of potassium tert-butoxide were added and the reaction mixture was
stirred further at RT overnight. For work-up, the reaction mixture
was diluted with water and acidified with 1N aqueous hydrochloric
acid, and the solid formed was filtered off. The solid was washed
with water and ethyl acetate, and dried under reduced pressure at
50.degree. C. overnight. This gave 736 mg (85% of theory) of the
target compound.
LC-MS (Method 1): R.sub.t=0.70 min; MS (ESIpos): m/z=348
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (t, 3H),
3.45 (s, 3H), 4.17 (q, 2H), 7.42-7.47 (m, 1H), 7.51-7.55 (m, 1H),
7.83-7.86 (m, 1H), 8.32 (s, 1H), 11.71 (s, 1H).
Example 8A
Ethyl
2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,-
4-tetrahydropyrimidine-5-carboxylate
##STR00057##
Preparation and purification of the target compound were analogous
to Example 7A. Starting with 1.95 g (10.26 mmol) of
5-amino-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one from Example 2A
and 2.66 g (10.26 mmol) of ethyl
3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate, 2.84 g (77% of
theory) of the title compound were obtained.
LC-MS (Method 4): R.sub.t=1.62 min; MS (ESIpos): m/z=358
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (t, 3H),
1.29 (s, 6H), 3.17 (s, 3H), 4.17 (q, 2H), 7.13 (d, 1H), 7.40 (dd,
1H), 7.51 (d, 1H), 8.25 (s, 1H), 11.65-11.71 (m, 1H).
Example 9A
Ethyl
1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate
##STR00058##
1.76 g (6.79 mmol) of ethyl
3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate and 1.00 g (6.79
mmol) of 1-methyl-1H-benzimidazol-5-amine [for preparation see: US
2008/0090856, Ex. B23] in 51 ml of ethanol were heated to reflux
for 2 h. Thereafter, at RT, 0.76 g (6.79 mmol) of potassium
tert-butoxide were added and the reaction mixture was heated to
reflux for a further 3 h. Water was added, and the reaction mixture
was acidified with 1N aqueous hydrochloric acid. The aqueous phase
was concentrated, dichloromethane/methanol (1:1) was added and the
solid formed was filtered off. The filtrate was concentrated,
MTBE/ethyl acetate (1:1) was added, and the solid formed was
filtered off, washed with ethyl acetate and then dried at
50.degree. C. under reduced pressure. This gave 1.55 g (73% of
theory) of the title compound.
LC-MS (Method 4): R.sub.t=1.00 min; MS (ESIpos): m/z=315
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (t, 3H),
4.03 (s, 3H), 4.18 (q, 2H), 7.62-7.68 (m, 1H), 7.94-8.00 (m, 1H),
8.00-8.03 (m, 1H), 8.35 (s, 1H), 9.24 (br.s, 1H), 11.73 (s,
1H).
Example 10A
5-Amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one
hydrochloride
##STR00059##
33.2 g (160 mmol) of
1,3-dimethyl-5-nitro-1,3-dihydro-2H-benzimidazol-2-one
(preparation: see WO 2007/120339, Example 2, page 33) in 1790 ml of
ethanol (only partly dissolved) were hydrogenated in the presence
of 8.8 g of palladium catalyst (10% on activated carbon, moistened
with 50% water) at RT and hydrogen standard pressure. After
completion of conversion (6 h), the catalyst was removed by
filtration through kieselguhr. 45 ml of a hydrogen chloride
solution (4N in dioxane) were added to the filtrate, and the
mixture was concentrated to dryness on a rotary evaporator. The
residue was dried under high vacuum. This gave 31.8 g (91% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.18 min; m/z=178 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.33 (s, 3H),
3.34 (s, 3H), 7.06-7.15 (m, 2H), 7.23 (d, 1H), 10.29 (br.s,
3H).
Example 11A
Ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,-
2,3,4-tetrahydropyrimidine-5-carboxylate
##STR00060##
52.80 g (247.1 mmol) of the compound from Example 10A and 64.07 g
(247.1 mmol) ethyl 3-ethoxy-2-[(ethoxycarbonyl)carbamoyl]acrylate
(for preparation see: Senda, Shigeo; Hirota, Kosaku; Notani,
Jiyoji, Chemical & Pharmaceutical Bulletin (1972), 20(7),
1380-8) were initially charged in 2 l of ethanol, and 51.7 ml
(370.7 mmol) of triethylamine were added. The thick suspension
formed was heated to reflux temperature for 1.5 h, forming a clear
solution. After cooling to about 60.degree. C., 27.73 g (247.1
mmol) of potassium tert-butoxide were added. The reaction mixture
was heated again to reflux temperature and stirred at this
temperature for a further 7 h. After cooling to RT, about half the
solvent was removed on a rotary evaporator. The reaction mixture
was then poured into 7.5 l of 1N hydrochloric acid. The solid
formed was filtered off, washed with 800 ml of water and dried
under high vacuum. This gave 71.7 g (85% of theory) of the title
compound.
LC-MS (Method 1): R.sub.t=0.63 min; m/z=345 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.22 (t, 3H),
3.30 (s, 3H), 3.37 (s, 3H), 4.17 (q, 2H), 7.19 (dd, 1H), 7.25 (d,
1H), 7.37 (d, 1H), 8.26 (s, 1H).
Example 12A
Ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazol-
idin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate
##STR00061##
A mixture of 400 mg (1.16 mmol) of ethyl
2,4-dioxo-1-[4-(2-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carboxylate from Example 3A, 353 mg (1.39 mmol) of
2-methyl-3-(trifluoromethyl)benzyl bromide, 321 mg (2.32 mmol) of
potassium carbonate and 193 mg (1.16 mmol) of potassium iodide in
16 ml of acetonitrile was stirred at 60.degree. C. for 18 hours.
The mixture was then cooled to 20.degree. C., and 50 ml of water
were added. The product formed was filtered off with suction,
washed with a little diethyl ether and dried under high vacuum. 537
mg (89% of theory) of the target compound were obtained.
LC-MS (Method 2): R.sub.t=1.05 min; m/z=517 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.22 (t, 3H), 2.48 (s,
3H), 3.42 (m, 2H), 3.87 (m, 2H), 4.19 (q, 2H), 5.08 (s, 2H), 7.08
(s, 1H), 7.30-7.40 (m, 2H), 7.46 (d, 2H), 7.59 (d, 1H), 7.68 (d,
2H), 8.39 (s, 1H).
Example 13A
Ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxa-
zolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate
##STR00062##
The preparation was carried out analogously to Example 12A from 200
mg (0.58 mmol) of ethyl
2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrim-
idine-5-carboxylate from Example 4A and 146.6 mg (0.58 mmol) of
2-methyl-3-(trifluoromethyl)benzyl bromide. Yield: 37 mg (12% of
theory).
LC-MS (Method 4): R.sub.t=2.36 min; m/z=518 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.23 (t, 3H), 2.45 (s,
3H), 4.10 (m, 2H), 4.20 (q, 2H), 4.45 (m, 2H), 5.05 (s, 2H),
7.30-7.40 (m, 2H), 7.52-7.62 (m, 3H), 7.70 (d, 2H), 8.41 (s,
1H).
Example 14A
Ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-
-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carboxylate (R Enantiomer)
##STR00063##
A solution of 5.0 g (15.1 mmol) of ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetr-
ahydropyrimidine-5-carboxylate from Example 5A, 6.73 g (25.7 mmol)
of triphenylphosphine and 3.66 g (18.1 mmol) of
(1S)-4-(trifluoromethyl)indan-1-ol was initially charged under
argon in 240 ml of DMF/THF 2:1 (v/v) and cooled to -15.degree. C.
4.76 ml (24.15 mmol) of diisopropyl azodicarboxylate was slowly
added dropwise at such a rate that the temperature of the reaction
mixture did not rise above -10.degree. C. At the end of the
addition, the mixture was stirred at -10.degree. C. for another 1
h, then warmed to RT and poured onto 1.3 l of water. The mixture
was extracted twice with 300 ml each time of ethyl acetate. The
combined organic phases were washed with a saturated aqueous sodium
chloride solution, dried over magnesium sulfate and freed of the
solvent on a rotary evaporator. The residue (18 g) was purified in
two chromatography steps: first using a 200 g silica gel column
with dichloromethane/acetone 97.5:2.5 as the mobile phase. The
resulting product-containing fractions were concentrated and the
residue was applied again to a 200 g silica gel column. 2.5 l of
cyclohexane/ethyl acetate 1:1 as mobile phase were used to elute
further impurities, then the desired product was eluted from the
column with dichloromethane/methanol 95:5. This gave 3.40 g (44% of
theory) of the title compound in 95% purity (the NMR showed about
5% ethyl acetate). A further 920 mg were obtainable by a new
purification of a mixed fraction. Total yield: 4.32 g (56% of
theory).
LC-MS (Method 1): R.sub.t=1.15 min; m/z=516 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.31 (t,
3H), 2.37-2.49 (m, 1H), 2.59 (dtd, 1H), 3.14 (dt, 1H), 3.40 (s,
3H), 3.42-3.53 (m, 1H), 4.29 (q, 2H), 6.54-6.68 (m, 1H), 7.06 (d,
1H), 7.17 (d, 1H), 7.22 (s, 1H), 7.26-7.36 (m, 2H), 7.49 (d, 1H),
8.28 (s, 1H).
Example 15A
Ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3--
[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate (R Enantiomer)
##STR00064##
3.05 g (8.86 mmol) of ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carboxylate from Example 11A, 2.15 g (10.63
mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 6.97 g (26.6 mmol)
of triphenylphosphine were initially charged under argon in THF/DMF
1:1 (1.7 l) and cooled to -15.degree. C. 3.48 ml (17.71 mmol) of
diisopropyl azodicarboxylate were added gradually. Subsequently,
the reaction mixture was stirred at RT for another 30 min. While
cooling with ice, a further 0.8 equivalent (1.39 ml, 6.86 mmol) of
diisopropyl azodicarboxylate was added dropwise and the reaction
mixture was stirred at RT for 1 h. The reaction mixture was cooled
to -40.degree. C., 1M hydrochloric acid was added, and the mixture
was diluted with ethyl acetate and stirred vigorously for a few
minutes. The organic phase was separated, washed twice with 1M
sodium carbonate solution and once with saturated sodium chloride
solution, dried over sodium sulfate and concentrated on a rotary
evaporator. MTBE was added to the residue and the mixture was
stirred at RT overnight, then stirred with ice bath cooling for 20
min. The solid formed was filtered off with suction and washed with
cold MTBE. The whole filtrate was concentrated and purified by
means of preparative HPLC (Method 5). This gave 2.90 g (62% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.05 min; m/z=529 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta.=1.36 (t, 3H),
2.42-2.55 (m, 1H), 2.57-2.71 (m, 1H), 3.12-3.24 (m, 1H), 3.43 (s,
3H), 3.43-3.58 (m, 1H), 3.45 (s, 3H), 4.33 (q, 2H), 6.60-6.73 (m,
1H), 6.99 (s, 1H), 7.07 (s, 2H), 7.30-7.42 (m, 2H), 7.54 (d, 2H),
8.36 (s, 1H).
Example 16A
Ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1-
R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (R Enantiomer)
##STR00065##
8.00 g (23.03 mmol) of ethyl
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-te-
trahydropyrimidine-5-carboxylate from Example 7A, 5.12 g (25.33
mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 10.27 g (39.15
mmol) of triphenylphosphine were initially charged in 317 ml of THF
and 317 ml of DMF and cooled to 5.degree. C. 7.25 ml (36.85 mmol)
of diisopropyl azodicarboxylate were added in portions. The cooling
bath was removed and the mixture was stirred at RT for 1 h. For
workup, 200 ml of 1N hydrochloric acid were added and the mixture
was stirred vigorously for 5 min. 400 ml of ethyl acetate were
added. After stirring vigorously for 10 minutes, the organic phase
was removed. The aqueous phase was extracted once more with 400 ml
of ethyl acetate. The combined organic phases were washed twice
with 100 ml each time of a saturated sodium carbonate solution,
then with 100 ml of a saturated sodium chloride solution, then
dried over sodium sulfate and concentrated on a rotary evaporator.
400 ml of MTBE were added to the residue, and the mixture was
stirred while cooling with an ice bath for 30 min. The solid formed
was filtered off with suction and washed twice with cold MTBE. The
combined filtrates were concentrated and the residue was purified
by means of flash chromatography (cyclohexane/ethyl acetate
1:2.fwdarw.1:4). The product thus obtained was recrystallized from
acetonitrile and dried under high vacuum. This gave 6.3 g (50% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.18 min; m/z=532 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.31 (t,
3H), 2.37-2.49 (m, 1H), 2.53-2.65 (m, 1H), 3.08-3.20 (m, 1H),
3.40-3.52 (m, 1H), 3.45 (s, 3H), 4.29 (q, 2H), 6.56-6.68 (m, 1H),
7.09-7.18 (m, 1H), 7.25-7.36 (m, 3H), 7.44 (s, 1H), 7.47-7.54 (m,
1H), 8.29 (s, 1H).
Example 17A
Ethyl
1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)ben-
zyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
##STR00066##
1.00 g (3.18 mmol) of ethyl
1-(1-methyl-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine--
5-carboxylate from Example 9A were initially charged in DMF (8 ml),
and 886 mg (3.50 mmol) of
1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 879 mg (6.36
mmol) of potassium carbonate and 53 mg (0.32 mmol) of potassium
iodide were added. Subsequently, the reaction mixture was left to
stir at 60.degree. C. for 5 h. The mixture cooled to RT, water was
added and the precipitate was filtered off with suction, washed
with water and ethanol/MTBE, and dried under reduced pressure at
50.degree. C. This gave 1.06 g (68% of theory) of the title
compound.
LC-MS (Method 1): R.sub.t=0.93 min; m/z=487 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.23 (t, 3H),
2.46 (s, 3H), 3.89 (s, 3H), 4.19 (q, 2H), 5.09 (s, 2H), 7.32-7.46
(m, 3H), 7.60 (d, 1H), 7.71 (d, 1H), 7.89 (d, 1H), 8.33 (s, 1H),
8.46 (s, 1H).
Example 18A
Ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl--
2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylat-
e
##STR00067##
Preparation and purification of the title compound were analogous
to Example 17A. Starting with 500 mg (1.39 mmol) of ethyl
2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tet-
rahydropyrimidine-5-carboxylate from Example 8A and 389 mg (1.53
mmol) of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 571
mg (77% of theory) of the title compound were obtained.
LC-MS (Method 1): R.sub.t=1.11 min; m/z=530 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (s, 6H),
2.46 (s, 3H), 3.18 (s, 3H), 3.30 (s, 3H), 4.20 (q, 2H), 5.08 (s,
2H), 7.15 (d, 1H), 7.34-7.39 (m, 2H), 7.44-7.49 (m, 1H), 7.53-7.56
(m, 1H), 7.58-7.63 (m, 1H), 8.42 (s, 1H).
Example 19A
Ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl--
3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylate
##STR00068##
To a solution of 14.95 g (43.42 mmol) of ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carboxylate from Example 3A in DMF (200 ml)
were added 12.00 g (86.84 mmol) of potassium carbonate, 12.09 g
(47.76 mmol) of 2-methyl-3-(trifluoromethyl)benzyl bromide and
0.721 g (4.34 mmol) of potassium iodide, and the reaction mixture
was left to stir at 80.degree. C. for 3 h. Subsequently, the
mixture was cooled to RT, water was added and the precipitate
formed was filtered off. The solid was washed successively with
water and MTBE, and dried under reduced pressure at 50.degree. C.
This gave 21.04 g (94% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.07 min; m/z=517 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.23 (t, 3H),
2.46 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 4.20 (q, 2H), 5.09 (s,
2H), 7.23-7.30 (m, 2H), 7.32-7.43 (m, 3H), 7.58-7.62 (m, 1H), 8.42
(s, 1H).
Example 20A
Ethyl
3-(2,3-dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate
##STR00069##
95 mg (0.69 mmol) of potassium carbonate and 91 mg (0.38 mmol) of
2,3-dichlorobenzyl bromide were added to 100 mg (0.34 mmol) of
ethyl
1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
from Example 6A in acetonitrile, and the reaction mixture was
stirred at 60.degree. C. overnight. The mixture was concentrated
and the residue was purified by filtration through 500 mg of silica
gel using cyclohexane/ethyl acetate in a ratio of 2:1. This gave,
after concentration of the eluate and drying under reduced
pressure, 137 mg (88% of theory) of the target compound.
LC-MS (Method 1): R.sub.t=1.19 min; m/z=449 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.23 (t, 3H), 3.81 (s,
3H), 4.20 (q, 2H), 5.09 (s, 2H), 7.04-7.09 (m, 2H), 7.21 (dd, 1H),
7.32 (t, 1H), 7.43-7.49 (m, 2H), 7.58 (dd, 1H), 8.39 (s, 1H).
Example 21A
3-(2,3-Dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxylic acid
##STR00070##
135 mg (0.30 mmol) of ethyl
3-(2,3-dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropy-
rimidine-5-carboxylate from Example 20A in a mixture of 2.0 ml of
acetic acid and 1.0 ml of concentrated hydrochloric acid were
stirred at 110.degree. C. overnight. Under reduced pressure, the
reaction mixture was concentrated to about a third, and after
addition of water a solid formed which was filtered off, washed
with water and dried under reduced pressure. This gave 61 mg (48%
of theory) of the target compound.
LC-MS (Method 2): R.sub.t=1.28 min; m/z=421 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=3.81 (s, 3H), 5.12 (s,
2H), 7.03-7.09 (m, 2H), 7.24 (dd, 1H), 7.33 (t, 1H), 7.43-7.49 (m,
2H), 7.58 (dd, 1H), 8.41 (s, 1H), 12.69 (br. s., 1H).
Example 22A
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(tr-
ifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-c-
arboxylic acid (R Enantiomer)
##STR00071##
3.40 g (6.60 mmol) of the compound from Example 14A in 44 ml of
glacial acetic acid and 22 ml of concentrated hydrochloric acid
were stirred at reflux temperature for 1 h. After cooling slightly
(about 60.degree. C.), the mixture was fully concentrated under
reduced pressure. 50 ml of isopropanol were added to the amorphous
residue and the mixture was heated to reflux for 15 min, in the
course of which a solid formed. The suspension was then cooled to
10.degree. C. and then the solid was filtered off with suction. The
solid was washed twice with 15 ml each time of isopropanol,
filtered off with suction and dried under HV. This gave 2.53 g (79%
of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.12 min; m/z=488 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.40-2.52
(m, 1H), 2.59-2.72 (m, 1H), 3.12-3.25 (m, 1H), 3.41 (s, 3H),
3.44-3.56 (m, 1H), 6.58-6.69 (m, 1H), 7.04-7.11 (m, 1H), 7.15-7.21
(m, 1H), 7.24 (br.s, 1H), 7.29-7.38 (m, 2H), 7.53 (s, 1H), 8.54 (s,
1H), 12.39 (br. s, 1H).
Specific rotation .beta..sub.D.sup.20=+135.3.degree. (methanol,
c=0.43).
Example 23A
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)--
4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-
e-5-carboxylic acid (R Enantiomer)
##STR00072##
4.20 g (7.79 mmol) of ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[4-(t-
rifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5--
carboxylate from Example 15A were stirred with 40 ml of glacial
acetic acid and 20 ml of conc. hydrochloric acid at reflux
temperature for 1 h. The reaction mixture was cooled to RT, then
diluted with 300 ml of water. The solid formed was filtered off
with suction, washed with a little water and dried under HV. The
solid thus obtained was stirred with 45 ml of toluene. At first it
dissolved completely, but after a few minutes a crystalline solid
formed. The mixture was cooled to 0.degree. C. and stirred at this
temperature for 30 min. Subsequently, the solid was filtered off,
washed with 5 ml of toluene and dried under HV. This gave 3.17 g
(81% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.06 min; m/z=501 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.38-2.46 (m,
1H), 2.46-2.60 (m, 1H partially hidden under DMSO signal), 3.10
(dt, 1H), 3.23-3.35 (m, 1H partially hidden under DMSO-signal),
3.31 (s, 4H), 3.36 (s, 3H), 6.36-6.60 (m, 1H), 7.12-7.30 (m, 2H),
7.31-7.43 (m, 2H), 7.48-7.58 (m, 2H), 8.38 (s, 1H), 12.71 (br.s,
1H).
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.42-2.53
(m, 1H), 2.60-2.72 (m, 1H), 3.11-3.25 (m, 1H), 3.39 (s, 3H), 3.41
(s, 3H), 3.45-3.55 (m, 1H), 6.59-6.71 (m, 1H), 6.94 (br. s, 1H),
7.04 (s, 2H), 7.28-7.41 (m, 2H), 7.54 (d, 1H), 8.57 (s, 1H), 12.45
(br. S, 1H).
In an analogous experiment, it was possible to isolate a fraction
with 99% purity. For this batch, the specific optical rotation
measured was:
Specific optical rotation: .alpha..sub.D.sup.20=+110.6.degree.,
(methanol, c=0.405 g/100 ml).
Example 24A
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4-(-
trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-
-carboxylic acid (R Enantiomer)
##STR00073##
6.20 g (11.3 mmol) of the compound from Example 16A in 150 ml of
glacial acetic acid/conc. hydrochloric acid 2:1 were heated to
120.degree. C. (bath temperature) for 1 h. After cooling to RT, the
reaction mixture was poured into 1 l of ice-water. The product
formed was filtered off with suction. The solid was stirred with
diethyl ether, filtered off with suction again and dried under HV.
This gave 5.04 g (88% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.14 min; m/z=504 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.39-2.53
(m, 1H), 2.60-2.72 (m, 1H), 3.12-3.24 (m, 1H), 3.42-3.56 (m, 4H),
6.58-6.71 (m, 1H), 7.15 (d, 1H), 7.26-7.38 (m, 3H), 7.45 (s, 1H),
7.50-7.58 (m, 1H), 8.55 (s, 1H).
For further batches of the title compound, which have been prepared
analogously, the following additional analytical data have been
collected: .alpha..sub.D.sup.20 [chloroform,
c=0.365]=+148.6.degree..
Example 25A
3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin-1-
-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
##STR00074##
532 mg (1.03 mmol) of ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate from
Example 12A were dissolved in 14 ml of glacial acetic acid and 7 ml
of conc. hydrochloric acid, and the mixture was stirred at
60.degree. C. After HPLC confirmed complete conversion of the
reaction (reaction time 5.5 hours), the mixture was diluted with 30
ml of water and the precipitate formed was filtered off with
suction. The mixture was then purified by preparative HPLC (Method
11). This gave, after concentration of the product-containing
fractions under reduced pressure, 338 mg (66% of theory) of the
product.
LC-MS (Method 4): R.sub.t=2.19 min; m/z=489 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=2.45 (s, 3H), 3.44 (m,
2H), 3.9 (m, 2H), 5.1 (s, 2H), 7.08 (s, 1H), 7.32 (t, 1H), 7.38 (d,
1H), 7.45 (d, 2H), 7.60 (d, 1H), 7.65 (d, 2H), 8.42 (s, 1H), 12.70
(br. s, 1H).
Example 26A
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tri-
fluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid
##STR00075##
5.60 g (10.84 mmol) of ethyl
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tr-
ifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
from Example 19A were initially charged in 78 ml of glacial acetic
acid and 39 ml of conc. hydrochloric acid and stirred at
120.degree. C. for 1 h. Subsequently, water was added to the
mixture, which had cooled to RT, and the precipitate was filtered
off with suction. The solid was washed successively with water and
MTBE and then dried at 50.degree. C. under reduced pressure. This
gave 5.11 g (96% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.98 min; m/z=489 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.47 (s, 3H),
3.31 (s, 3H), 3.37 (s, 3H), 5.11 (s, 2H), 7.22-7.30 (m, 2H),
7.33-7.43 (m, 3H), 7.59-7.63 (m, 1H), 8.45 (s, 1H), 12.73 (br.s,
1H).
Example 27A
1-(1-Methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2-
,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
##STR00076##
The preparation and purification of the title compound were in
analogy to Example 26A. Starting with 170 mg (0.35 mmol) of ethyl
1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]--
2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate from Example
77, 124 mg (77% of theory) of the title compound were obtained.
LC-MS (Method 1): R.sub.t=0.90 min; m/z=459 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.47 (s, 3H),
3.89 (s, 3H), 5.12 (s, 2H), 7.33-7.40 (m, 1H), 7.41-7.46 (m, 2H),
7.59-7.63 (m, 1H), 7.71 (d, 1H), 7.86-7.89 (m, 1H), 8.33 (s, 1H),
8.50 (s, 1H), 12.72 (br.s, 1H).
Example 28A
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo--
2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid
##STR00077##
The preparation and purification of the title compound were in
analogy to Example 26A. Starting with 200 mg (0.38 mmol) of ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-
-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
from Example 53, 153 mg (80% of theory) of the title compound were
obtained.
LC-MS (Method 1): R.sub.t=1.07 min; m/z=502 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.29 (s, 6H),
2.47 (s, 3H), 3.17 (s, 3H), 5.11 (s, 2H), 7.15 (d, 1H), 7.32-7.42
(m, 2H), 7.46 (dd, 1H), 7.54 (d, 1H), 7.58-7.64 (m, 1H), 8.45 (s,
1H), 12.73 (br.s, 1H).
Example 29A
3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidi-
n-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
##STR00078##
The preparation and purification were carried out analogously to
Example 25A from 37 mg (0.07 mmol) of ethyl
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxazolid-
in-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate from
Example 13A. Yield: 15 mg (42% of theory).
LC-MS (Method 1): R.sub.t=1.08 min; m/z=490 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=2.49 (s, 3H), 4.10 (m,
2H), 4.47 (m, 2H), 5.10 (s, 2H), 7.32 (t, 1H), 7.40 (d, 1H),
7.51-7.62 (m, 3H), 7.70 (d, 2H), 8.44 (s, 1H), 12.7 (br. s,
1H).
Example 30A
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4--
tetrahydropyrimidine-5-carbonitrile
##STR00079##
A mixture of 1.00 g (4.71 mmol) of ethyl
(2-cyano-3-ethoxyprop-2-enoyl)carbamate (for preparation see:
Senda, Shigeo, Hirota, Kosaku, Notani, Jiyoji; Chemical &
Pharmaceutical Bulletin (1972), 20(7), 1380-8) and 835 mg (4.71
mmol) of 5-amino-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one in
5 ml of acetonitrile and 10 ml of DMF was stirred at reflux
temperature overnight. After cooling to RT, the mixture was diluted
with 150 ml of diethyl ether and the precipitate was filtered off.
The filter residue was stirred with 10 ml of methanol, and the
solid was filtered off, washed with a little methanol and ether and
dried under high vacuum. This gave 703 mg (45% of theory) of the
title compound.
LC-MS (Method 1): R.sub.t=0.53 min; m/z=298 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.30 (br. s,
3H), 3.36 (br. s, 3H), 7.17 (dd, 1H), 7.23-7.28 (m, 1H), 7.34 (d,
1H), 8.77 (s, 1H).
Example 31A
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetra-
hydropyrimidine-5-carbonitrile
##STR00080##
A mixture of 1.00 g (4.71 mmol) of ethyl
(2-cyano-3-ethoxyprop-2-enoyl)carbamate and 774 mg (4.71 mmol) of
6-amino-3-methyl-1,3-benzoxazol-2(3H)-one in 10 ml of acetonitrile
and 10 ml of DMF was stirred at reflux temperature overnight. After
cooling to RT, the solid was filtered off, washed with acetonitrile
and dried under HV. This solid was taken up in 20 ml of DMF, 985
.mu.l (7.07 mmol) of triethylamine were added and the solution was
stirred at 80.degree. C. for 4 h. After cooling to RT, the mixture
was diluted with 200 ml of water. The solid was filtered off and
washed with water. The entire filtrate was allowed to stand at
20.degree. C. overnight, once again resulting in the precipitation
of a solid. The solid was filtered off and dried under high vacuum.
This gave 276 mg (19% of theory) of the title compound.
LC-MS (Method 19): R.sub.t=1.21 min; m/z=285 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.38 (s, 3H),
7.34-7.40 (m, 2H), 7.56 (d, 1H), 8.78 (s, 1H), 12.14 (br. s,
1H).
Example 32A
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tet-
rahydropyrimidine-5-carbonitrile
##STR00081##
A mixture of 1.00 g (4.71 mmol) of ethyl
(2-cyano-3-ethoxyprop-2-enoyl)carbamate and 849 mg (4.71 mmol) of
6-amino-3-methyl-1,3-benzothiazol-2(3H)-one (for preparation: see
J. Het. Chem. 1992, 29 (5), 1069-1076, Example 8b) in 28 ml of
acetonitrile was heated in the microwave at 180.degree. C. for 2 h.
After cooling to RT, the solvent was removed on a rotary
evaporator. The residue was stirred with 10 ml of methanol for 30
min. Subsequently, the solid was filtered off, washed with a little
methanol and with ether and then dried under HV. This gave 859 mg
(49% of theory, purity 81%) of the title compound.
LC-MS (Method 1): R.sub.t=0.62 min; ES neg: m/z=299
(M-H).sup.-.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.45 (s, 3H),
7.46 (s, 1H), 7.50 (d, 1H), 7.81 (d, 1H), 8.81 (s, 1H), 12.16
(br.s, 1H).
Example 33A
2,4-Dioxo-1-[4-(2-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-
e-5-carbonitrile
##STR00082##
A suspension of 600 mg (2.83 mmol) of ethyl
(2-cyano-3-ethoxyprop-2-enoyl)carbamate and 501 mg (2.83 mmol) of
1-(4-aminophenyl)imidazolidin-2-one (for preparation see: P.
Stabile et al., Tetrahedron Letters 2010, 51 (24), 3232-3235) in 15
ml of acetonitrile was heated in the microwave at 180.degree. C.
for 1 h. After cooling to RT, the solid was filtered off with
suction, washed with acetonitrile and dried under high vacuum. The
crude product thus obtained (540 mg, 55% of theory, purity about
55%) was used without any additional purification.
LC-MS (Method 1): R.sub.t=0.46 min; m/z=298 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.40-3.48 (m,
2H), 3.84-3.93 (m, 2H), 7.10 (s, 1H), 7.39 (d, 2H), 7.66 (d, 2H),
8.76 (s, 1H), 12.09 (br. s, 1H).
Example 34A
2,4-Dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrimi-
dine-5-carbonitrile
##STR00083##
A suspension of 500 mg (2.36 mmol) of ethyl
(2-cyano-3-ethoxyprop-2-enoyl)carbamate and 420 mg (2.36 mmol) of
3-(4-aminophenyl)-1,3-oxazolidin-2-one (for preparation: see
WO2010/019903, p. 222, Method 38; or Farmaco Sci. Ed. (1969), 179)
in 15 ml of acetonitrile was heated in the microwave at 180.degree.
C. for 1 h. After cooling to RT, about 2/3 of the solvent were
removed on a rotary evaporator. The solid formed was filtered off
with suction, washed with acetonitrile and ether and dried under
high vacuum. The crude product thus obtained (470 mg, 51% of
theory, purity about 77%) was used without any additional
purification.
LC-MS (Method 1): R.sub.t=0.50 min; m/z=299 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.07-4.15 (m,
2H), 4.44-4.52 (m, 2H), 7.49 (d, 2H), 7.68 (d, 2H), 8.78 (s, 1H),
12.12 (br. s., 1H).
Example 35A
6-Methyl-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,-
3,4-tetrahydropyrimidine-5-carbonitrile
##STR00084##
145 mg (0.88 mmol) of 6-amino-3-methyl-1,3-benzoxazol-2(3H)-one
were initially charged in 13 ml of ethanol, and 200 mg (0.88 mmol)
ethyl (2-cyano-3-ethoxybut-2-enoyl)carbamate (for preparation see:
Senda, Shigeo; Hirota, Kosaku; Notani, Jiyoji, Chemical &
Pharmaceutical Bulletin (1972), 20(7), 1380-8) were added and the
mixture was heated at reflux temperature for 2 h. After cooling to
about 60.degree. C., 99 mg (0.88 mmol) of potassium tert-butoxide
were added and the reaction mixture was stirred further at reflux
temperature for 1 h. The mixture was then cooled to about
60.degree. C. and stirred into 50 ml of cold 0.5N aqueous
hydrochloric acid. The solid was filtered off with suction, washed
with water and dried under high vacuum. This gave 186 g (65% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.59 min; MS (ESIpos): m/z=299
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.08 (s, 3H),
3.38 (s, 3H), 7.31-7.36 (m, 1H), 7.37-7.43 (m, 1H), 7.53 (d, 1H),
12.11 (s, 1H).
Example 36A
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-N'-hydroxy-2,4-dio-
xo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahyd-
ropyrimidine-5-carboximidamide (R Enantiomer)
##STR00085##
Under argon, 58 .mu.l (415 .mu.mol) of triethylamine were added to
a solution of 29 mg (415 .mu.mol) of hydroxylamine hydrochloride in
1.1 ml of DMSO. The mixture was stirred at RT for 10 min and then
filtered. 40 mg (83 .mu.mol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-
-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carbonitrile (Example 1) were added to the filtrate, and this
mixture was heated at 75.degree. C. overnight. After cooling to RT,
the reaction mixture was separated by preparative HPLC (Method 6).
This gave 15 mg (35% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=0.90 min; MS (ESIpos): m/z=515
(M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.39-2.51
(m, 1H), 2.61 (ddd, 1H), 3.10-3.22 (m, 1H), 3.35 (s, 3H), 3.37 (s,
3H), 3.42-3.54 (m, 1H), 6.56-6.67 (m, 1H), 6.98 (d, 1H), 7.11 (br.
d, 1H), 7.19 (br. s., 1H), 7.28-7.39 (m, 2H), 7.52 (d, 1H), 7.57
(br. s, 2H), 8.97 (br. s, 1H).
Analogously to Example 36A, the following Examples 37A to 41A were
prepared from the corresponding nitriles and 5 equivalents of
hydroxylamine hydrochloride (Table 1).
TABLE-US-00001 TABLE 1 IUPAC name/structure Example (Yield)
Precursor Analytical data 37A 1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-
benzimidazol-5-yl)-N'-hydroxy-3-[2-
methyl-3-(trifluoromethyl)benzyl]-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5- carboximidamide ##STR00086##
yield: 285 mg (71% of theory) Ex. 6 LC/MS (Method 1): R.sub.t =
0.88 min; m/z = 503 (M + H).sup.+ 38A N'-hydroxy-3-[2-methyl-3-
(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-
oxoimidazolidin-1-yl)phenyl]-1,2,3,4-
tetrahydropyrimidine-5-carboximidamide ##STR00087## yield: 298 mg
(65% of theory) Ex. 4 LC/MS (Method 1): R.sub.t = 0.86 min; m/z =
503 (M + H).sup.+ 39A 1-(3,4-dimethoxyphenyl)-N'-hydroxy-3-[2-
methyl-3-(trifluoromethyl)benzyl]-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5- carboximidamide ##STR00088##
yield: 360 mg (74% of theory) Ex. 9 LC/MS (Method 1): R.sub.t =
0.89 min; m/z = 479 (M + H).sup.+ 40A
N'-hydroxy-1-(4-methoxyphenyl)-3-[2-
methyl-3-(trifluoromethyl)benzyl]-2,4-
dioxo-1,2,3,4-tetrahydropyrimidine-5- carboximidamide ##STR00089##
yield: 92 mg (72% of theory) Ex. 11 LC/MS (Method 2): R.sub.t =
1.12 min; m/z = 449 (M + H).sup.+ 41A
N'-hydroxy-1-(3-methyl-2-oxo-2,3-
dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-
[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-
inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5- carboximidamide
##STR00090## yield: 19 mg (42% of theory) Ex. 2 LC/MS (Method 1):
R.sub.t = 0.93 min; m/z = 502 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CD.sub.2Cl.sub.2): .delta. [ppm] = 2.37-2.50 (m, 1H), 2.55-2.69 (m,
1H), 3.09- 3.22 (m, 1H), 3.38 (s, 3H), 3.41-3.53 (m, 1H), 6.53-
6.68 (m, 1H), 7.03 (d, 1H), 7.17-7.44 (m, 6H), 7.51 (d, 1H), 8.82
(br. s, 1H).
Example 42A
N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,-
3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboximidamide
##STR00091##
Under argon, 1.3 ml (9.35 mmol) of triethylamine were added to a
solution of 650 mg (9.35 mmol) of hydroxylamine hydrochloride in 23
ml of DMSO. The mixture was stirred at RT for 10 min and then
filtered. 1.00 g (1.9 mmol, purity 90%) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxazolid-
in-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(Example 5) was added to the filtrate, and this mixture was heated
at 75.degree. C. overnight. After cooling, the reaction mixture was
poured into 100 ml of 0.1N aqueous hydrochloric acid. The
precipitated solid was filtered off, washed with water and dried.
This solid was stirred with 30 ml of acetonitrile, resulting in the
dissolution of the product, whereas an impurity remained
undissolved. The impurity was filtered off, the filtrate was
concentrated and the residue was dried under HV. This gave 1.0 g
(about 95% pure, quant. yield) of the title compound.
LC/MS (Method 13): R.sub.t=0.87 min; m/z=504 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.47 (s, 3H),
4.11 (t, 2H), 4.48 (t, 2H), 5.13 (s, 2H), 7.32-7.44 (m, 2H),
7.54-7.65 (m, 3H), 7.73 (d, 2H), 8.60 (br. s, 1H).
Example 43A
Ethyl
2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-3-[(1R)-4-(trifluo-
romethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carbox-
ylate (R Enantiomer)
##STR00092##
Under argon, 9.00 g (26.1 mmol) of the compound from Example 4A,
6.85 g (33.9 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 12.31
g (46.9 mmol) of triphenylphosphine were initially charged in a
mixture of 359 ml of anhydrous THF and 359 ml of anhydrous DMF and
cooled to 0.degree. C. 8.43 g (41.7 mmol) of diisopropyl
azodicarboxylate were added dropwise. The reaction mixture was then
allowed to warm to RT and was stirred at RT for 1 h. 100 ml of 1 N
aqueous hydrochloric acid were added. The mixture was stirred for
another 15 min and diluted with 1 l of ethyl acetate. The organic
phase was separated off, washed three times with in each case 800
ml of 1 N aqueous hydrochloric acid, then twice with in each case
300 ml of 1 N aqueous sodium carbonate solution and once with 400
ml of saturated aqueous sodium chloride solution, dried over sodium
sulfate and concentrated on a rotary evaporator. The solid that
remained was stirred in a mixture of 300 ml of MTBE and 200 ml of
2-propanol, isolated by filtration, washed with 100 ml of MTBE and
dried under high vacuum. This gave 8.2 g (54% of theory, purity
91%; with 6% of triphenylphosphine oxide as main impurity).
LC-MS (Method 1): R.sub.t=1.11 min; MS (ESIpos): m/z=530
(M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.23 (t,
3H), 2.29-2.41 (m, 1H), 2.50 (dtd, 1H), 3.00-3.12 (m, 1H),
3.33-3.45 (m, 1H), 3.93-4.02 (m, 2H), 4.20 (q, 2H), 4.35-4.45 (m,
2H), 6.53 (br. t, 1H), 7.15-7.33 (m, 4H), 7.41 (d, 1H), 7.59 (d,
2H), 8.21 (s, 1H).
Example 44A
2,4-Dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-3-[(1R)-4-(trifluorometh-
yl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid (R Enantiomer)
##STR00093##
7.6 g (13.1 mmol) of the compound from Example 43A, 82.7 ml of
glacial acetic acid and 41.4 ml of conc. hydrochloric acid were
heated at reflux temperature for 1 h. After cooling to RT, the
reaction mixture was stirred into 1500 ml of water. The solid
formed was filtered off, washed with a little water and dried under
high vacuum. The residue was then dissolved in a little DMSO and
purified by preparative HPLC (Method 5). This gave 4.75 g (72% of
theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.09 min; MS (ESIpos): m/z=502
(M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.31-2.45
(m, 1H), 2.57 (dtd, 1H), 3.02-3.18 (m, 1H), 3.31-3.50 (m, 1H),
3.88-4.06 (m, 2H), 4.33-4.49 (m, 2H), 6.56 (br. s., 1H), 7.16-7.36
(m, 4H), 7.45 (d, 1H), 7.62 (d, 2H), 8.46 (s, 1H).
WORKING EXAMPLES
Example 1
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)--
4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-
e-5-carbonitrile (R Enantiomer)
##STR00094##
49 mg (0.17 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carbonitrile from Example 30A, 36.7 mg
(0.18 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 73.5 mg (0.28
mmol) of triphenylphosphine were initially charged in 1 ml of THF
and 2 ml of DMF at RT. 53.3 mg (0.26 mmol) of diisopropyl
azodicarboxylate were added and the reaction mixture was stirred at
RT for 1 hour. Subsequently, 0.15 ml of 1N aqueous hydrochloric
acid were added and the mixture was stirred for a further 15 min.
The mixture was separated by preparative HPLC (Method 6). This gave
34 mg (43% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.06 min., m/z=482 (M+H).sup.+
.sup.1H-NMR (500 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.24-2.41
(m, 1H), 2.49-2.59 (m, 1H), 2.98-3.15 (m, 1H), 3.30 (s, 3H), 3.32
(s, 3H), 3.36-3.47 (m, 1H), 6.39-6.59 (m, 1H), 6.82 (s, 1H),
6.88-7.03 (m, 2H), 7.18-7.33 (m, 2H), 7.44 (d, 1H), 7.90 (s,
1H).
Example 2
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(tr-
ifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-c-
arbonitrile (R Enantiomer)
##STR00095##
49 mg (0.17 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetr-
ahydropyrimidine-5-carbonitrile from Example 31A, 38.3 mg (0.19
mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 76.9 mg (0.29 mmol)
of triphenylphosphine were initially charged in 1 ml of THF and 2
ml of DMF at RT, 55.8 mg (0.28 mmol) of diisopropyl
azodicarboxylate were added and the mixture was stirred at RT for 1
h. 0.15 ml of 1 N aqueous hydrochloric acid was added, and the
mixture was stirred for 15 minutes. The mixture was separated by
preparative HPLC (Method 6). This gave 38 mg (47% of theory) of the
title compound.
LC/MS (Method 1): R.sub.t=1.10 min; m/z=469 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.31-2.49
(m, 1H), 2.56-2.69 (m, 1H), 3.03-3.21 (m, 1H), 3.35-3.43 (s, 3H),
3.44-3.53 (m, 1H), 6.49-6.69 (m, 1H), 7.07 (s, 1H), 7.11-7.16 (m,
1H), 7.17-7.22 (m, 1H), 7.33 (s, 2H), 7.45-7.60 (m, 1H), 7.95 (s,
1H).
Example 3
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4-(-
trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-
-carbonitrile (R Enantiomer)
##STR00096##
49 mg (0.16 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-te-
trahydropyrimidine-5-carbonitrile from Example 32A, 36.3 mg (0.18
mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 72.8 mg (0.28 mmol)
of triphenylphosphine were initially charged in 1 ml of THF and 2
ml of DMF at RT, 52.8 mg (0.26 mmol) of diisopropyl
azodicarboxylate were added and the mixture was stirred at RT for 1
h. 0.15 ml of 1N aqueous hydrochloric acid was added. The mixture
was stirred for 15 minutes and then separated by preparative HPLC
(Method 6). This gave 29 mg (37% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.17 min., m/z=485 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.32-2.48
(m, 1H), 2.53-2.74 (m, 1H), 3.02-3.23 (m, 1H), 3.41-3.54 (m, 1H),
3.45 (s, 3H), 6.57 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.30-7.37
(m, 2H), 7.41 (s, 1H), 7.52 (d, 1H), 7.96 (s, 1H).
Example 4
3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin-1-
-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
##STR00097##
58 mg (0.2 mmol) of
2,4-dioxo-1-[4-(2-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carbonitrile from Example 33A were initially charged in 2 ml
of acetonitrile at RT, 54.3 mg (0.22 mmol) of
1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 53.9 mg (0.39
mmol) of potassium carbonate and 16.2 mg (0.1 mmol) of potassium
iodide were added and the mixture was stirred at reflux temperature
for 3 h. At RT, DMSO was added, and the reaction solution was
separated by preparative HPLC (Method 6). This gave 36 mg (39% of
theory) of the title compound.
LC/MS (Method 2): R.sub.t=1.21 min., m/z=470 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.46-2.55 (m,
2H), 2.88-3.02 (m, 2H), 4.14 (s, 2H), 6.19 (s, 1H), 6.35-6.55 (m,
4H), 6.62-6.82 (m, 3H), 8.02 (s, 1H).
Example 5
3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidi-
n-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
##STR00098##
150 mg (0.38 mmol) of
2,4-dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrim-
idine-5-carbonitrile from Example 34A were initially charged in 5
ml of acetonitrile at RT, 145 mg (0.57 mmol) of
1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 158.5 mg (1.15
mmol) of potassium carbonate and 31.7 mg (0.19 mmol) of potassium
iodide were added and the mixture was stirred at reflux temperature
for 3 h. At RT, the reaction solution was diluted with ethyl
acetate and extracted with 1N aqueous hydrochloric acid. The
organic phase was washed first with saturated aqueous sodium
carbonate solution, then with saturated aqueous sodium chloride
solution, then dried over sodium sulfate and concentrated. The
residue was stirred with 4 ml of methanol, and the solid was
filtered off with suction, washed with methanol and diethyl ether
and dried. This gave 126 mg (69% of theory) of the title
compound.
LC-MS (Method 2): R.sub.t=1.26 min., m/z=471 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.45 (s, 3H),
4.10 (t, 2H), 4.47 (t, 2H), 4.97-5.24 (m, 2H), 7.31-7.39 (m, 1H),
7.42-7.47 (m, 1H), 7.53 (d, 2H), 7.61 (d, 1H), 7.71 (d, 2H), 8.98
(s, 1H).
Example 6
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tri-
fluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
##STR00099##
150 mg (0.45 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carbonitrile from Example 30A were
initially charged in 5 ml of acetonitrile at RT, 171 mg (0.67 mmol)
of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene, 186 mg
(1.35 mmol) of potassium carbonate and 37.3 mg (0.23 mmol) of
potassium iodide were added and the mixture was stirred at reflux
temperature for 3 h. At RT, the reaction solution was diluted with
ethyl acetate and extracted with 1N aqueous hydrochloric acid. The
organic phase was washed with saturated aqueous sodium carbonate
solution and with saturated aqueous sodium chloride solution, dried
over sodium sulfate and concentrated. The residue was stirred with
3 ml of methanol, and the solid was filtered off with suction,
washed with methanol and diethyl ether and dried. This gave 160 mg
(76% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.26 min., m/z=470 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.45 (s, 3H),
3.34 (s, 3H), 3.37 (s, 3H), 5.04-5.15 (m, 2H), 7.17-7.24 (m, 1H),
7.25-7.30 (m, 1H), 7.31-7.40 (m, 2H), 7.41-7.49 (m, 1H), 7.61 (d,
1H), 8.96 (s, 1H).
Example 7
3-[4-Chloro-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1-
H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(Racemate)
##STR00100##
60 mg (0.19 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidine-5-carbonitrile from Example 30A, 34.8 mg
(0.21 mmol) of 4-chloroindan-1-ol (racemate) and 83.7 mg (0.32
mmol) of triphenylphosphine were initially charged in 1.1 ml of THF
and 2.2 ml of DMF at RT, 60.7 mg (0.30 mmol) of diisopropyl
azodicarboxylate were added and the reaction mixture was stirred at
RT for 1 h. Subsequently, 0.15 ml of 1N aqueous hydrochloric acid
was added and the mixture was stirred for a further 15 min. The
mixture was separated by preparative HPLC (Method 6). This gave 26
mg (31% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.05 min., m/z=448 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.34-2.45
(m, 1H), 2.52-2.66 (m, 1H), 2.95-3.07 (m, 1H), 3.26-3.37 (m, 1H),
3.38 (s, 3H), 3.40 (s, 3H), 6.52-6.66 (m, 1H), 6.90 (s, 1H),
6.94-7.09 (m, 3H), 7.15 (t, 1H), 7.21-7.32 (m, 1H), 7.97 (s,
1H).
Example 8
3-[4-Chloro-2,3-dihydro-1H-inden-1-yl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3-b-
enzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(Racemate)
##STR00101##
60 mg (0.20 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-te-
trahydropyrimidine-5-carbonitrile from Example 32A, 37.1 mg (0.22
mmol) of 4-chloroindan-1-ol (racemate) and 89.1 mg (0.34 mmol) of
triphenylphosphine were initially charged in 1.2 ml of THF and 2.3
ml of DMF at RT, 64.6 mg (0.32 mmol) of diisopropyl
azodicarboxylate were added and the reaction mixture was stirred at
RT for 1 h. Subsequently, 0.15 ml of 1N aqueous hydrochloric acid
was added and the mixture was stirred for 15 min. The mixture was
separated by preparative HPLC (Method 6). This gave 26 mg (28% of
theory) of the title compound.
LC/MS (Method 3): R.sub.t=2.54 min, m/z=451 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.29-2.44
(m, 1H), 2.59 (m, 1H), 2.91-3.11 (m, 1H), 3.23-3.37 (m, 1H), 3.45
(s, 3H), 6.59 (br. s, 1H), 7.04 (d, 1H), 7.11-7.19 (m, 2H),
7.20-7.30 (m, 2H), 7.41 (s, 1H), 7.95 (s, 1H).
Example 9
1-(3,4-Dimethoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-
,2,3,4-tetrahydropyrimidine-5-carbonitrile
##STR00102##
150 mg (0.45 mmol) of
1-(3,4-dimethoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonit-
rile (preparation: see U.S. Pat. No. 4,266,056, example 13, column
11) were initially charged in 5 ml of acetonitrile at RT, 168.8 mg
(0.67 mmol) of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene,
184.4 mg (1.33 mmol) of potassium carbonate and 36.9 mg (0.22 mmol)
of potassium iodide were added and the mixture was stirred at
reflux temperature for 3 h. At RT, the reaction solution was
diluted with ethyl acetate and extracted with 1N aqueous
hydrochloric acid. The organic phase was washed with saturated
aqueous sodium carbonate solution and with saturated aqueous sodium
chloride solution, dried over sodium sulfate and concentrated. The
residue was stirred with 2 ml of methanol, and the solid was
filtered off with suction, washed with a little methanol and then
with diethyl ether and dried. This gave 126 mg (59% of theory) of
the title compound.
LC/MS (Method 1): R.sub.t=1.12 min, m/z=446 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.45 (s, 3H),
3.76 (s, 3H), 3.80 (s, 3H), 5.07 (s, 2H), 6.99-7.09 (m, 2H), 7.17
(d, 1H), 7.30-7.46 (m, 2H), 7.61 (d, 1H), 8.93 (s, 1H).
Example 10
3-(2,3-Dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyr-
imidine-5-carbonitrile
##STR00103##
300 mg (1.23 mmol) of
1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
were initially charged in 12 ml of acetonitrile at RT, 325.5 mg
(1.36 mmol) of 1-(bromomethyl)-2,3-dichlorobenzene, 340.9 mg (2.47
mmol) of potassium carbonate and 102.4 mg (0.62 mmol) of potassium
iodide were added and the mixture was stirred at reflux temperature
for 5 h. The reaction mixture was cooled to RT, filtered and
concentrated under reduced pressure. The residue was stirred with 2
ml of boiling methanol. After cooling to RT, the precipitate was
filtered off with suction, washed with a little isopropanol and
dried. This gave 423 mg (81% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.15 min., m/z=402 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.80 (s, 3H),
5.08 (s, 2H), 6.97-7.13 (m, 2H), 7.23-7.35 (m., 2H), 7.38-7.48 (m,
2H), 7.54-7.64 (m, 1H), 8.87-9.09 (m, 1H).
Example 11
3-[2-Chloro-3-(trifluoromethyl)benzyl]-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3-
,4-tetrahydropyrimidine-5-carbonitrile
##STR00104##
300 mg (1.23 mmol) of
1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
were initially charged in 12 ml of acetonitrile at RT, 371.1 mg
(1.36 mmol) of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene,
340.9 mg (2.47 mmol) of potassium carbonate and 102.4 mg (0.62
mmol) of potassium iodide were added and the mixture was stirred at
reflux temperature for 5 h. Water was added, and the reaction
solution was extracted with ethyl acetate. The organic phase was
dried over sodium sulfate and concentrated. The residue was stirred
with 2 ml of isopropanol, and the solid was filtered off with
suction, washed with a little isopropanol and dried. This gave
295.4 mg (54% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.16 min; m/z=436 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.75-3.88 (m,
3H), 5.06-5.24 (m, 2H), 7.00-7.15 (m, 2H), 7.39-7.45 (m, 2H),
7.47-7.56 (m, 1H), 7.65 (d, 1H), 7.81 (d, 1H), 8.74-9.13 (m,
1H).
Example 12
6-Methyl-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(-
1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrim-
idine-5-carbonitrile (R Enantiomer)
##STR00105##
186 mg (0.62 mmol) of
6-methyl-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2-
,3,4-tetrahydropyrimidine-5-carbonitrile from Example 35A, 151.3 mg
(0.75 mmol) of (1S)-4-(trifluoromethyl)indan-1-ol and 278.1 mg
(1.06 mmol) of triphenylphosphine were initially charged in 3.3 ml
of THF and 6.6 ml of DMF at RT, 201.8 mg (1.0 mmol) of diisopropyl
azodicarboxylate were added and the reaction mixture was stirred at
RT overnight. 5 ml of 1 N aqueous hydrochloric acid were then
added, and the mixture was stirred at RT for 15 min and diluted
with ethyl acetate, and the phases were separated. The organic
phase was washed successively with water, 0.5 M aqueous sodium
carbonate solution and saturated aqueous sodium chloride solution,
dried over sodium sulfate and concentrated. The crude product was
purified by preparative HPLC (Method 6). This gave 50 mg (15% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.10 min., m/z=483 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.21 (s,
3H), 2.31-2.44 (m, 1H), 2.52-2.66 (m, 1H), 3.05-3.18 (m, 1H),
3.37-3.50 (m, 1H), 3.41 (s, 3H), 6.54 (br. s., 1H), 6.94-7.16 (m,
3H), 7.26-7.37 (m, 2H), 7.46-7.58 (m, 1H).
Example 13
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-(1H-tetrazol-5-y-
l)-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]pyrimidine-2,4(1H-
,3H)-dione (R Enantiomer)
##STR00106##
15 mg (0.03 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-
-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carbonitrile (R enantiomer) (Example 1) were initially charged
in 2 ml of toluene at RT. 0.78 mg (0.003 mmol) of di-n-butyltin
oxide and 28.7 mg (0.25 mmol) of trimethylsilyl azide were added,
and the mixture was stirred at reflux temperature for 5 h. After
cooling to RT, 2 ml of ethanol were added and the mixture was
stirred at RT for 1 h and concentrated. The residue was dissolved
in a little DMSO/acetonitrile 1:1 (v/v) and purified by preparative
HPLC (Method 6). This gave 10 mg (61% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.0 min., m/z=525 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.45-2.58
(m, 1H), 2.60-2.74 (m, 2H), 3.09-3.29 (m, 1H), 3.40 (s, 3H), 3.43
(s, 3H), 3.46-3.58 (m, 1H), 6.61-6.76 (m, 1H), 7.00 (br. s., 1H),
7.07 (br. s, 2H), 7.26-7.42 (m, 3H), 7.53 (d, 1H), 8.77 (s,
1H).
Example 14
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-(1H-tetrazol-5-yl)-3--
[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]pyrimidine-2,4(1H,3H)--
dione (R Enantiomer)
##STR00107##
18 mg (0.04 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(t-
rifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5--
carbonitrile (R enantiomer) (Example 2) were initially charged in 2
ml of toluene at RT. 1 mg (0.004 mmol) of di-n-butyltin oxide and
35.4 mg (0.31 mmol) of trimethylsilyl azide were added, and the
mixture was stirred at reflux temperature for 5 h. After cooling to
RT, 2 ml of ethanol were added and the mixture was stirred at RT
for 1 h and concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 11 mg (56% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.04 min., m/z=512 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.42-2.55
(m, 1H), 2.65 (d, 1H), 3.11-3.25 (m, 1H), 3.43 (s, 3H), 3.45-3.60
(m, 1H), 6.59-6.81 (m, 1H), 7.10 (d, 1H), 7.19-7.41 (m, 4H), 7.53
(d, 1H), 8.74 (s, 1H), 13.17-13.67 (m, 1H).
Example 15
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-5-(1H-tetrazol-5-yl)--
3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]pyrimidine-2,4(1H,3H-
)-dione (R Enantiomer)
##STR00108##
14 mg (0.03 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4--
(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine--
5-carbonitrile (R enantiomer) (Example 3) were initially charged in
1.5 ml of toluene at RT. 0.72 mg (0.003 mmol) of di-n-butyltin
oxide and 26.6 mg (0.23 mmol) of trimethylsilyl azide were added,
and the mixture was stirred at reflux temperature for 5 h. After
cooling to RT, 1.5 ml of ethanol were added and the mixture was
stirred at RT for 1 h and concentrated. The residue was dissolved
in a little DMSO/acetonitrile 1:1 (v/v) and purified by preparative
HPLC (Method 6). This gave 10 mg (62% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.08 min., m/z=528 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.42-2.57
(m, 1H), 2.59-2.77 (m, 1H), 3.10-3.28 (m, 1H), 3.47 (s, 3H), 6.69
(br. s, 1H), 7.17 (d, 1H), 7.27-7.41 (m, 3H), 7.45-7.61 (m, 2H),
8.74 (s, 1H), 13.42 (br. s, 1H).
Example 16
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1-
H-benzimidazol-5-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Racemate)
##STR00109##
26 mg (0.06 mmol) of
3-[4-chloro-2,3-dihydro-1H-inden-1-yl]-1-(1,3-dimethyl-2-oxo-2,3-dihydro--
1H-benzimidazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitril-
e from Example 7 were initially charged in 3 ml of toluene at RT.
1.45 mg (0.006 mmol) of di-n-butyltin oxide and 53.5 mg (0.46 mmol)
of trimethylsilyl azide were added, and the mixture was stirred at
reflux temperature for 5 h. After cooling to RT, 3 ml of ethanol
were added and the mixture was stirred at RT for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 20 mg (70% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=0.96 min; m/z=491 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.37-2.56
(m, 1H), 2.64 (m, 1H), 2.95-3.15 (m, 1H), 3.32-3.37 (m, 1H), 3.40
(s, 3H), 3.43 (s, 3H), 6.64-6.80 (m, 1H), 6.95-7.19 (m, 5H), 7.25
(d, 1H), 8.76 (s, 1H), 13.19-13.66 (m, 1H).
Example 17
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1-
H-benzimidazol-5-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 1)
##STR00110##
Enantiomer eluting first from the chromatographic separation of 13
mg of the compound from Example 16 on a chiral phase (Method 14).
2.6 mg of enantiomer 1 were obtained.
Chiral analytical HPLC (Method 15) R.sub.t=5.84 min. 100% ee
LC/MS (Method 1): R.sub.t=0.96 min., m/z=491 (M+H).sup.+
Example 18
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1-
H-benzimidazol-5-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 2)
##STR00111##
Enantiomer eluting last from the chromatographic separation of 13
mg of the compound from Example 16 on a chiral phase (Method 14).
1.9 mg of enantiomer 2 were obtained.
Chiral analytical HPLC (Method 15) R.sub.t=6.42 min. 100% ee
LC/MS (Method 1): R.sub.t=0.96 min; m/z=491 (M+H).sup.+.
Example 19
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tri-
fluoromethyl)benzyl]-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00112##
50 mg (0.11 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tr-
ifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitril-
e (Example 6) were initially charged in 1.5 ml of toluene at RT.
2.65 mg (0.011 mmol) of di-n-butyltin oxide and 36.8 mg (0.32 mmol)
of trimethylsilyl azide were added and the mixture was stirred at
reflux temperature for 4 h. 73.6 mg (0.64 mmol) of trimethylsilyl
azide were added in two portions, and the mixture was stirred at
reflux temperature for a total of 24 h. After cooling to RT, 0.9 ml
of ethanol were added and the mixture was stirred at RT for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 26 mg (48% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=0.96 min; m/z=513 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.35 (s, 3H),
3.38 (s, 3H), 4.95-5.45 (m, 2H), 7.30 (d, 2H), 7.33-7.40 (m, 1H),
7.42-7.52 (m, 2H), 7.61 (d, 1H), 8.64 (s, 1H), 15.97-16.58 (m,
1H).
Example 20
1-(3,4-Dimethoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(1H-tetra-
zol-5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00113##
47.2 mg (0.11 mmol) of
1-(3,4-dimethoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo--
1,2,3,4-tetrahydropyrimidine-5-carbonitrile (Example 9) were
initially charged in 1.5 ml of toluene at RT. 2.64 mg (0.011 mmol)
of di-n-butyltin oxide and 36.6 mg (0.32 mmol) of trimethylsilyl
azide were added, and the mixture was stirred at reflux temperature
for 4 h. Additionally, 73.2 mg (0.64 mmol) of trimethylsilyl azide
were added in two portions, and the mixture was stirred at reflux
temperature for a total of 24 h. After cooling to RT, 0.9 ml of
ethanol were added and the mixture was stirred at RT for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 41 mg (78% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.0 min., m/z=489 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.78 (s, 3H),
3.82 (s, 3H), 5.20 (s, 2H), 7.07-7.16 (m, 2H), 7.24 (d, 1H),
7.32-7.39 (m, 1H), 7.47 (d, 1H), 7.61 (d, 1H), 8.59 (s, 1H),
16.12-16.49 (m, 1H).
Example 21
3-[2-Methyl-3-(trifluoromethyl)benzyl]-1-[4-(2-oxoimidazolidin-1-yl)phenyl-
]-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00114##
32 mg (0.07 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (Example
4) were initially charged in 1 ml of toluene at RT. 1.7 mg (0.007
mmol) of di-n-butyltin oxide and 23.6 mg (0.21 mmol) of
trimethylsilyl azide were added, and the mixture was stirred at
reflux temperature overnight. 47.2 mg (0.42 mmol) of trimethylsilyl
azide were added in two portions, and the mixture was stirred at
reflux temperature for a total of 48 hours. After cooling to RT,
0.6 ml of ethanol were added and the mixture was stirred at RT for
1 h and concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 23 mg (65% of theory) of the title
compound.
LC/MS (Method 2): R.sub.t=1.11 min; m/z=513 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.44 (t, 2H),
3.81-4.02 (m, 2H), 5.20 (s, 2H), 7.11 (s, 1H), 7.31-7.40 (m, 1H),
7.45-7.55 (m, 3H), 7.61 (d, 1H), 7.67-7.76 (m, 2H), 8.37-8.80 (m,
1H), 16.04-16.39 (m, 1H).
Example 22
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-b-
enzothiazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Racemate)
##STR00115##
26 mg (0.06 mmol) of
3-[4-chloro-2,3-dihydro-1H-inden-1-yl]-1-(3-methyl-2-oxo-2,3-dihydro-1,3--
benzothiazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(racemate) (Example 8) were initially charged in 3 ml of toluene at
RT. 1.39 mg (0.006 mmol) of di-n-butyltin oxide and 51.6 mg (0.45
mmol) of trimethylsilyl azide were added, and the mixture was
stirred at reflux temperature for 5 h. After cooling to RT, 3 ml of
ethanol were added and the mixture was stirred at RT for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 22 mg (80% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.04 min., m/z=494 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.39-2.53
(m, 1H), 2.57-2.72 (m, 1H), 2.98-3.11 (m, 1H), 3.24-3.41 (m, 1H),
3.47 (s, 3H), 6.71 (br. s., 1H), 7.03-7.10 (m, 1H), 7.11-7.20 (m,
2H), 7.25 (d, 1H), 7.36 (d, 1H), 7.51 (br. s., 1H), 8.69-8.80 (m,
1H), 13.27-13.63 (m, 1H).
Example 23
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-b-
enzothiazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 1)
##STR00116##
Enantiomer eluting first from the chromatographic separation of 17
mg of the compound from Example 22 on a chiral phase (Method 16).
7.2 mg of enantiomer 1 were obtained.
Chiral analytical HPLC (Method 17) R.sub.t=9.25 min; 100% ee
LC/MS (Method 1): R.sub.t=1.05 min; m/z=494 (M+H).sup.+.
Example 24
3-(4-Chloro-2,3-dihydro-1H-inden-1-yl)-1-(3-methyl-2-oxo-2,3-dihydro-1,3-b-
enzothiazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 2)
##STR00117##
Enantiomer eluting last from the chromatographic separation of 17
mg of the compound from Example 22 on a chiral phase (Method 16).
8.7 mg of enantiomer 2 were obtained.
Chiral analytical HPLC (Method 17) R.sub.t=10.38 min; 94% ee
LC/MS (Method 1): R.sub.t=1.05 min; m/z=494 (M+H).sup.+.
Example 25
3-[2-Methyl-3-(trifluoromethyl)benzyl]-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phe-
nyl]-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00118##
50 mg (0.11 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1,3-oxazolid-
in-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
(Example 5) were initially charged in 1.5 ml of toluene at RT. 2.65
mg (0.011 mmol) of di-n-butyltin oxide and 36.7 mg (0.32 mmol) of
trimethylsilyl azide were added and the mixture was stirred at
reflux temperature overnight. 73.4 mg (0.64 mmol) of trimethylsilyl
azide were added in two portions, and the mixture was stirred at
reflux temperature for a total of 30 h. After cooling to RT, 0.9 ml
of ethanol were added and the mixture was stirred at RT for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 31 mg (57% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=0.99 min; m/z=514 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.12 (t, 2H),
4.40-4.61 (m, 2H), 5.20 (s, 2H), 7.31-7.39 (m, 1H), 7.49 (d, 1H),
7.58-7.65 (m, 3H), 7.73 (d, 2H), 8.64 (s, 1H), 16.04-16.53 (m,
1H).
Example 26
3-[2-Chloro-3-(trifluoromethyl)benzyl]-1-(4-methoxyphenyl)-5-(1H-tetrazol--
5-yl)pyrimidine-2,4(1H,3H)-dione
##STR00119##
100 mg (0.23 mmol) of
3-[2-chloro-3-(trifluoromethyl)benzyl]-1-(4-methoxyphenyl)-2,4-dioxo-1,2,-
3,4-tetrahydropyrimidine-5-carbonitrile (Example 11) were initially
charged in 2 ml of toluene at RT. 5.7 mg (0.023 mmol) of
di-n-butyltin oxide and 79.31 mg (0.69 mmol) of trimethylsilyl
azide were added, and the mixture was stirred at reflux temperature
overnight. After cooling to RT, 2 ml of ethanol were added at RT
and the mixture was stirred for 1 h and concentrated. The residue
was dissolved in a little DMSO/acetonitrile 1:1 (v/v) and purified
by preparative HPLC (Method 6). This gave 69 mg (59% of theory) of
the title compound.
LC/MS (Method 1): R.sub.t=1.08 min; m/z=479 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.32 (s, 3H),
5.26 (s, 2H), 6.93-7.16 (m, 2H), 7.41-7.58 (m, 3H), 7.69 (d, 1H),
7.81 (d, 1H), 8.62 (s, 1H), 16.12-16.54 (m, 1H).
Example 27
3-(2,3-Dichlorobenzyl)-1-(4-methoxyphenyl)-5-(1H-tetrazol-5-yl)pyrimidine--
2,4(1H,3H)-dione
##STR00120##
100 mg (0.25 mmol) of
3-(2,3-dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropy-
rimidine-5-carbonitrile (Example 10) were initially charged in 2 ml
of toluene at RT. 6.19 mg (0.025 mmol) of di-n-butyltin oxide and
85.93 mg (0.75 mmol) of trimethylsilyl azide were added, and the
mixture was stirred at reflux temperature overnight. After cooling
to RT, 2 ml of ethanol were added and the mixture was stirred for 1
h and concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 75 mg (68% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.02 min; m/z=445 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.32 (br. s,
3H), 5.22 (s, 2H), 6.96-7.19 (m, 2H), 7.29-7.37 (m, 2H), 7.48-7.54
(m, 2H), 7.56-7.63 (m, 1H), 8.60 (s, 1H), 16.21-16.43 (m, 1H).
Example 28
3-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitr-
ile (Racemate)
##STR00121##
The title compound was prepared analogously to Example 2 from 230.0
mg (0.81 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetr-
ahydropyrimidine-5-carbonitrile from Example 31A and 162.6 (0.89
mmol) of 5-chloro-1,2,3,4-tetrahydronaphthalen-1-ol. This gave 180
mg (32% of theory, purity about 64%) of the title compound which
was used without additional purification for the preparation of
Example 29.
MS (DCI-NH.sub.3, Method 12): m/z=466 [M+NH.sub.3+H].sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.71-1.88
(m, 1H), 2.04-2.20 (m, 2H), 2.29-2.45 (m, 1H), 2.62-2.78 (m, 1H),
3.02 (d, 1H), 3.40 (s, 3H), 6.20 (br. s, 1H), 6.90 (d, 2H), 7.07
(m, 1H), 7.24 (d, 2H, 7.98 (s, 1H).
Example 29
3-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzoxazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Racemate)
##STR00122##
90 mg (0.13 mmol) of
3-(5-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihy-
dro-1,3-benzoxazol-6-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonit-
rile (Example 28) were initially charged in 6.7 ml of toluene at
RT. 3.19 mg (0.013 mmol) of di-n-butyltin oxide and 118.27 mg (1.03
mmol) of trimethylsilyl azide were added, and the mixture was
stirred at reflux temperature for 5 h. After cooling to RT, 6.7 ml
of ethanol were added and the mixture was stirred for 1 h and
concentrated. The residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 42 mg (67% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.03 min; m/z=492 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.81-1.96
(m, 1H), 2.12-2.31 (m, 2H), 2.42-2.60 (m, 1H), 2.80 (d, 1H), 3.11
(d, 1H), 3.48 (s, 3H), 6.17-6.52 (m, 1H), 6.98 (d, 1H), 7.06-7.21
(m, 2H), 7.29 (d, 3H), 8.81 (s, 1H), 13.26-13.64 (m, 1H).
Example 30
3-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzoxazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 1)
##STR00123##
Enantiomer eluting first from the chromatographic separation of 31
mg of the compound from Example 29 on a chiral phase (Method 18).
Owing to solvent impurities, the resulting product was purified by
means of preparative HPLC (Method 5). 7.0 mg of enantiomer 1 were
obtained.
Chiral analytical HPLC (Method 17) R.sub.t=7.31 min; 100% ee
LC/MS (Method 1): R.sub.t=1.04 min; m/z=492 (M+H).sup.+.
Example 31
3-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-(3-methyl-2-oxo-2,3-dihyd-
ro-1,3-benzoxazol-6-yl)-5-(1H-tetrazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(Enantiomer 2)
##STR00124##
Enantiomer eluting last from the chromatographic separation of 31
mg of the compound from Example 29 on a chiral phase (Method 18).
Owing to solvent impurities, the resulting product was purified by
means of preparative HPLC (Method 5). 7.0 mg of enantiomer 2 were
obtained.
Chiral analytical HPLC (Method 17) R.sub.t=11.8 min; 99% ee
LC/MS (Method 1): R.sub.t=1.04 min; m/z=492 (M+H).sup.+.
Example 32
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-(5-oxo-4,5-dihyd-
ro-1,2,4-oxadiazol-3-yl)-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden--
1-yl]pyrimidine-2,4(1H,3H)-dione (R Enantiomer)
##STR00125##
10 mg (0.025 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-N'-hydroxy-2,4-di-
oxo-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahy-
dropyrimidine-5-carboximidamide from Example 36A were initially
charged in 0.5 ml of DMF at RT. 2.2 mg (0.028 mmol) of pyridine
were added, 3.5 mg (0.025 mmol) of isobutyl chloroformate were
added dropwise and the mixture was stirred at RT for 1 h. HPLC
control showed complete conversion into the intermediate. Ethyl
acetate and 1 N aqueous hydrochloric acid were added to the
mixture. The organic phase was separated off, washed with saturated
aqueous sodium chloride solution, dried over sodium sulfate and
concentrated on a rotary evaporator. The residue was dried under
high vacuum. The resulting intermediate was taken up in 2 ml of
xylene, 1.3 mg (0.005 mmol) of 1-ethyl-3-methyl-1H-imidazol-3-ium
hexafluorophosphate were added and the mixture was reacted in a
microwave at 200.degree. C. for 1 h. The reaction mixture was
concentrated and the residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 7 mg (51% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.02 min., m/z=539 (MS/ES.sup.-)
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.41-2.52
(m, 1H), 2.58-2.71 (m, 1H), 3.10-3.23 (m, 1H), 3.39 (s, 3H), 3.41
(s, 3H), 3.47 (d, 1H), 6.63 (br. s., 1H), 6.91-6.99 (m, 1H), 7.04
(s, 2H), 7.28-7.40 (m, 2H), 7.53 (d, 1H), 8.39 (s, 1H), 9.43-9.74
(m, 1H).
Example 33
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tri-
fluoromethyl)benzyl]-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)pyrimidine--
2,4(1H,3H)-dione
##STR00126##
285 mg (0.576 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-N'-hydroxy-3-[2-m-
ethyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5--
carboximidamide from Example 37A were initially charged in 10 ml of
DMF at RT. 49.4 mg (0.624 mmol) of pyridine were added, 77.5 mg
(0.576 mmol) of isobutyl chloroformate were added dropwise and the
mixture was stirred at RT for 1 h. HPLC control showed complete
conversion into the intermediate. The mixture was diluted with 100
ml of water, and the solid formed was filtered off with suction,
washed with water and dried in a vacuum cabinet at 60.degree. C.
The intermediate in 18 ml of acetonitrile was stirred in a
microwave at 190.degree. C. for 20 min, and the reaction mixture
was subsequently concentrated. The residue was stirred with 20 ml
of ethyl acetate, and the solid formed was filtered off with
suction and dried. This gave 205 mg (66% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=0.94 min, m/z=527 (MS/ES.sup.-)
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.95-5.31 (m,
2H), 7.23-7.31 (m, 2H), 7.34-7.39 (m, 1H), 7.41-7.46 (m, 2H), 7.61
(d, 1H), 8.41 (s, 1H), 12.36-12.70 (m, 1H).
Example 34
3-[2-Methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazo-
l-3-yl)-1-[4-(2-oxoimidazolidin-1-yl)phenyl]pyrimidine-2,4(1H,3H)-dione
##STR00127##
At RT, 51.6 mg (0.652 mmol) of pyridine were added to 298 mg (0.593
mmol) of
N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-ox-
oimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboximidamide
from Example 38A in 10 ml of DMF, 81.0 mg (0.593 mmol) of isobutyl
chloroformate were added dropwise and the mixture was stirred at RT
for 1 h. HPLC control showed complete conversion into the
intermediate. The mixture was diluted with 100 ml of water, and the
solid formed was filtered off with suction, washed with water and
dried in a vacuum cabinet at 60.degree. C. The intermediate in 18
ml of acetonitrile was stirred in a microwave at 180.degree. C. for
20 min. The reaction mixture was concentrated, the residue was
stirred with 20 ml of ethyl acetate and the solid formed was
filtered off with suction and dried. This gave 285 mg (84% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t=0.92 min, m/z=527 (MS/ES.sup.-)
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.43 (t, 2H),
3.89 (t, 2H), 5.12 (s, 2H), 7.11 (s, 1H), 7.35 (s, 1H), 7.40-7.52
(m, 3H), 7.60 (s, 1H), 7.69 (d, 2H), 8.29-8.51 (m, 1H), 12.50 (br.
s., 1H).
Example 35
3-[2-Methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,5-dihydro-1,2,4-oxadiazo-
l-3-yl)-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]pyrimidine-2,4(1H,3H)-dione
##STR00128##
36 mg (0.072 mmol) of
N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1-
,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboximidamide
from Example 42A were initially charged in 1.4 ml of DMF at RT, 6.2
mg (0.08 mmol) of pyridine were added, 9.8 mg (0.072 mmol) of
isobutyl chloroformate were added dropwise and the mixture was
stirred at RT for 1 h. HPLC control showed complete conversion into
the intermediate. The mixture was diluted with 20 ml of water, and
the solid formed was filtered off with suction, washed with water
and dried in a vacuum cabinet at 60.degree. C. The resulting
intermediate was stirred with 2 ml of xylene in a microwave at
200.degree. C. for 1 hour. The reaction mixture was concentrated
and the residue was dissolved in a little DMSO and purified by
preparative HPLC (Method 5). This gave 11 mg (29% of theory) of the
title compound.
LC/MS (Method 1): R.sub.t=1.0 min, m/z=528 (MS/ES.sup.-)
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=4.11 (t, 2H),
4.39-4.57 (m, 2H), 5.13 (s, 2H), 7.30-7.39 (m, 1H), 7.41-7.47 (m,
1H), 7.55-7.65 (m, 3H), 7.72 (d, 2H), 8.41 (s, 1H), 12.38-12.66 (m,
1H).
Example 36
1-(3,4-Dimethoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,-
5-dihydro-1,2,4-oxadiazol-3-yl)pyrimidine-2,4(1H,3H)-dione
##STR00129##
36 mg (0.075 mmol) of
1-(3,4-dimethoxyphenyl)-N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-
-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboximidamide from
Example 39A were initially charged in 1.45 ml of DMF at RT, 6.6 mg
(0.08 mmol) of pyridine were added, 10.3 mg (0.075 mmol) of
isobutyl chloroformate were added dropwise and the mixture was
stirred at RT for 1 h. HPLC control showed complete conversion into
the intermediate. The mixture was diluted with 20 ml of water. The
solid formed was filtered off with suction, washed with water and
dried in a vacuum cabinet at 60.degree. C. The resulting
intermediate was stirred with 2 ml of xylene and 100 .mu.l of
1-n-butyl-3-methylimidazolium hexafluorophosphate in a microwave at
200.degree. C. for 1 h. The reaction mixture was concentrated and
the residue was dissolved in a little DMSO and purified by
preparative HPLC (Method 5). This gave 20 mg (53% of theory) of the
title compound.
LC/MS (Method 1): R.sub.t=1.05 min, m/z=505 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.77 (s, 3H),
3.81 (s, 3H), 5.12 (s, 2H), 7.03-7.13 (m, 2H), 7.21 (s, 1H),
7.32-7.39 (m, 1H), 7.40-7.46 (m, 1H), 7.61 (d, 1H), 8.38 (s, 1H),
12.50 (br. s, 1H).
Example 37
1-(4-Methoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,5-di-
hydro-1,2,4-oxadiazol-3-yl)pyrimidine-2,4(1H,3H)-dione
##STR00130##
92 mg (0.168 mmol) of
N'-hydroxy-1-(4-methoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-
-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboximidamide from Example
40A were initially charged in 2.8 ml of DMF at RT. 14.6 mg (0.185
mmol) of pyridine were added, 23.0 mg (0.168 mmol) of isobutyl
chloroformate were then added dropwise at 0.degree. C. and the
mixture was stirred at RT for 40 min. HPLC control showed complete
conversion into the intermediate. 56.6 mg (0.59 mmol) of sodium
tert-butoxide were then added, and the mixture was stirred at RT
for 30 min. 15 ml of 1N aqueous hydrochloric acid were added. The
solid formed was filtered off with suction, washed with water,
stirred with 10 ml of diethyl ether, once more filtered off with
suction, washed with diethyl ether and dried. This gave 20 mg (23%
of theory) of the title compound.
LC/MS (Method 2): R.sub.t=1.28 min; m/z=475 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.81 (br. s,
3H), 5.12 (br. s, 2H), 7.07 (d, 2H), 7.36 (d, 1H), 7.41-7.52 (m,
3H), 7.61 (d, 1H), 8.27-8.54 (m, 1H), 12.35-12.62 (m, 1H).
Example 38
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-(5-oxo-4,5-dihydro-1,-
2,4-oxadiazol-3-yl)-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-
pyrimidine-2,4(1H,3H)-dione (R Enantiomer)
##STR00131##
17 mg (0.03 mmol) of
N'-hydroxy-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-
-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropy-
rimidine-5-carboximidamide from Example 41A were initially charged
in 0.7 ml of DMF at RT. 2.95 mg (0.04 mmol) of pyridine were added,
4.4 mg (0.03 mmol) of isobutyl chloroformate were added dropwise
and the mixture was stirred at RT for 1 h. HPLC control showed
complete conversion into the intermediate. Ethyl acetate and 1 N
aqueous hydrochloric acid were added to the mixture. The organic
phase was separated off, washed with saturated aqueous sodium
chloride solution, dried over sodium sulfate and concentrated on a
rotary evaporator. The residue was dried under high vacuum. The
resulting intermediate was taken up in 2 ml of xylene, 1.74 mg
(0.01 mmol) of 1-ethyl-3-methyl-1H-imidazol-3-ium
hexafluorophosphate were added and the mixture was reacted in a
microwave at 200.degree. C. for 1 h. The reaction mixture was
concentrated and the residue was dissolved in a little
DMSO/acetonitrile 1:1 (v/v) and purified by preparative HPLC
(Method 6). This gave 10 mg (56% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=1.06 min., m/z=526 (MS/ES.sup.-)
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.30-2.50
(m, 1H), 2.54-2.74 (m, 1H), 3.17 (m, 1H), 3.41 (s, 3H), 3.46 (d,
1H), 6.62 (br. s, 1H), 7.08 (d, 1H), 7.19 (d, 1H), 7.23-7.28 (m,
1H), 7.28-7.38 (m, 2H), 7.53 (d, 1H), 8.36 (s, 1H), 9.36-9.66 (m,
1H).
Example 39
3-[2-Methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,5-dihydro-1,2,4-thiadiaz-
ol-3-yl)-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]pyrimidine-2,4(1H,3H)-dion-
e
##STR00132##
531 mg (2.98 mmol) of thiocarbonyldiimidazole were added to a
solution of 1.00 g (1.99 mmol) of
N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-1-
,3-oxazolidin-3-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboximidamide
from Example 42A in 40 ml of anhydrous THF, and the resulting
mixture was stirred at RT for 30 min. The resulting suspension was
diluted with 100 ml of water. The solid was filtered off with
suction, washed with water and then dissolved in
dichloromethane/methanol 10:1. The solution was dried over sodium
sulfate and concentrated on a rotary evaporator. The residue was
dried under high vacuum (810 mg). 730 mg of this solid were taken
up in 29 ml of anhydrous THF, and 905 .mu.l (7.1 mmol) of boron
trifluoride/diethyl ether complex were added. The reaction mixture
was stirred at RT overnight and then poured into 200 ml of 0.1 N
aqueous hydrochloric acid. The solid formed was filtered off,
dissolved in a little DMSO and purified by preparative HPLC (Method
5). This gave 96 mg (15% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.04 min, m/z=546 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.48 (s, 3H),
4.11 (dd, 2H), 4.47 (dd, 2H), 5.13 (s, 2H), 7.36 (t, 1H), 7.44 (d,
1H), 7.55-7.64 (m, 3H), 7.71 (d, 2H), 8.41 (s, 1H), 12.76 (s,
1H).
Example 40
1-(3,4-Dimethoxyphenyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(5-oxo-4,-
5-dihydro-1,2,4-thiadiazol-3-yl)pyrimidine-2,4(1H,3H)-dione
##STR00133##
Under argon, 60 mg (0.125 mmol) of
1-(3,4-dimethoxyphenyl)-N'-hydroxy-3-[2-methyl-3-(trifluoromethyl)benzyl]-
-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboximidamide from
Example 39A were dissolved in 2.3 ml of THF. 33.5 mg (0.188 mmol)
of thiocarbonyldiimidazole were added and the mixture was stirred
at RT for 30 min. 53.4 mg (0.378 mmol) of boron trifluoride/diethyl
ether complex was added. The mixture was stirred at RT for 1 h and
at reflux temperature for 2 h, allowed to cool to RT, diluted with
DMSO and separated completely by preparative HPLC (Method 5). This
gave 6 mg (9% of theory) of the title compound.
LC/MS (Method 2): R.sub.t=1.34 min., m/z=521 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.77 (s, 3H),
3.80 (s, 3H), 4.96-5.28 (m, 2H), 7.04-7.11 (m, 2H), 7.21 (d, 1H),
7.32-7.39 (m, 1H), 7.40-7.45 (m, 1H), 7.61 (d, 1H), 8.37 (s, 1H),
12.76 (br. s, 1H).
Example 41
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(tr-
ifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-c-
arboxamide (R Enantiomer)
##STR00134##
200 mg (0.41 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(t-
rifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5--
carboxylic acid from Example 22A and 99.8 mg (0.74 mmol) of HOBt
were initially charged in 10 ml of DMF. 142 mg (0.74 mmol) of EDC
were added and the mixture was stirred at RT for 20 min. 2.1 ml of
ammonia (35% in water) were then added and the mixture was stirred
at RT for two hours. With vigorous stirring, 50 ml of water were
added, and the resulting precipitate was filtered off with suction
and dried under high vacuum. This gave 196 mg (94% of theory) of
the title compound.
LC/MS (Method 1): R.sub.t=1.03 min; m/z=487 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.39-2.53
(m, 1H), 2.61 (dtd, 1H), 3.07-3.22 (m, 1H), 3.41 (s, 3H), 3.41-3.53
(m, 1H), 5.70 (br. s, 1H), 6.51-6.71 (m, 1H), 7.06 (d, 1H), 7.18
(d, 1H), 7.24 (br. s, 1H), 7.27-7.36 (m, 2H), 7.51 (d, 1H), 7.97
(s, 1H), 8.46 (br. s, 1H).
Example 42
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)-2,4-dioxo-3-[(1R)-4-(-
trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5-
-carboxamide (R Enantiomer)
##STR00135##
The title compound was prepared analogously to Example 41 from 220
mg (0.41 mmol; purity 94%) of the compound from Example 24A and
aqueous ammonia. Yield: 190 mg (89% of theory).
LC/MS (Method 1): R.sub.t: 1.07 min; m/z=503 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.40-2.53
(m, 1H), 2.56-2.68 (m, 1H), 3.10-3.22 (m, 1H), 3.42-3.53 (m, 1H),
3.45 (s, 3H), 5.70 (br. s, 1H), 6.64 (br. s, 1H), 7.13 (d, 1H),
7.26-7.37 (m, 3H), 7.45 (br. s, 1H), 7.51 (d, 1H), 8.48 (br. s,
1H), 8.52 (s, 1H).
Example 43
1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)--
4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidin-
e-5-carboxamide (R Enantiomer)
##STR00136##
100 mg (0.2 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-
-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carboxylic acid from Example 23A and 37.8 mg (0.28 mmol) of
HOBt were initially charged in 5 ml of DMF. 53.6 mg (0.28 mmol) of
EDC were added and the mixture was stirred at RT for 20 min. 1 ml
of ammonia (35% in water) was then added. The reaction mixture was
stirred at RT for 4 h and then concentrated. The residue was
dissolved in a little DMSO and separated by preparative HPLC
(Method 6). This gave 40 mg (40% of theory) of the title
compound.
LC/MS (Method 1): R.sub.t=0.95 min; m/z=500 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.37-2.54
(m, 1H), 2.61 (m, 1H), 3.06-3.25 (m, 1H), 3.38 (s, 3H), 3.40 (s,
3H), 3.46 (d, 1H), 5.66-5.80 (m, 1H), 6.64 (br. s, 1H), 6.90-7.06
(m, 3H), 7.25-7.36 (m, 2H), 7.51 (d, 1H), 8.54 (s, 1H).
Example 44
Methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimi-
dazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)alaninate
(Racemate)
##STR00137##
43 mg (0.31 mmol) of methyl alaninate hydrochloride (racemate),
98.6 mg (0.31 mmol) of TBTU and 169 .mu.l (1.54 mmol) of
N-methylmorpholine were added to 150 mg (0.31 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
(Example 25A) in 3.75 ml of dichloromethane, and the mixture was
stirred at RT for 22 h. The mixture was concentrated to dryness on
a rotary evaporator and the residue was taken up in 1 ml of DMF and
5 ml of acetonitrile. The suspension formed was diluted with 50 ml
of water and stirred for 5 min. The solid was filtered off, washed
with water and dried under high vacuum. This gave 154 mg (83% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.09 min; m/z=574 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.38 (d, 3H),
2.47 (s, 3H), 3.43 (t, 2H), 3.65 (s, 3H), 3.85-3.92 (m, 2H), 4.52
(quin, 1H), 5.14 (s, 2H), 7.11 (s, 1H), 7.31-7.38 (m, 1H),
7.39-7.43 (m, 1H), 7.45-7.51 (m, 2H), 7.61 (d, 1H), 7.66-7.72 (m,
2H), 8.34 (s, 1H), 9.10 (d, 1H).
Example 45
N-({3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolid-
in-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)alanine
(Racemate)
##STR00138##
116 mg (0.2 mmol) of methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazoli-
din-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)alaninate
(racemate) from Example 44 were dissolved in 2 ml of acetic acid, 1
ml of conc. hydrochloric acid and 1 ml of water, and the mixture
was stirred at 60.degree. C. for 28 hours. The mixture was diluted
with 50 ml of water and the precipitate formed was filtered off
with suction. The product was dissolved and separated by
preparative HPLC (Method 8). This gave 62 mg (53% of theory) of the
title compound.
LC/MS (Method 4): R.sub.t=2.14 min m/z=560 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.37 (d, 3H),
3.43 (t, 2H), 3.83-3.96 (m, 2H), 4.43 (s, 1H), 5.02-5.23 (m, 2H),
7.11 (s, 1H), 7.32-7.42 (m, 2H), 7.48 (d, 2H), 7.61 (d, 1H), 7.70
(d, 2H), 8.27-8.40 (m, 1H), 9.13 (d, 1H), 12.93 (br. s., 1H).
Example 46
Methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trime-
thyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidin-5-yl}car-
bonyl)alaninate (Racemate)
##STR00139##
92 mg (0.48 mmol) of EDC and 73 mg (0.48 mmol) of HOBt were added
to 200 mg (0.40 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-oxo-
-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid from Example 28A in 2.2 ml of DMF, and the reaction mixture
was stirred at RT for 10 min. 62 mg (0.60 mmol) of DL-methyl
alaninate (racemate) and 0.10 ml (0.60 mmol) of
N,N-diisopropylethylamine were then added, and the reaction mixture
was stirred further at RT overnight. Water was then added, and the
mixture was filtered. The filter residue was washed with water and
dried under high vacuum at 50.degree. C. The resulting residue was
purified by Versaflash.RTM. silica gel chromatography
(dichloromethane/methanol gradient 120:1 to 20:1). This gave, after
concentration of the appropriate fractions and drying under reduced
pressure, 172 mg (73% of theory) of the target compound.
LC-MS (Method 1): R.sub.t=1.14 min; MS (ESIpos): m/z=587
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.30 (s, 6H), 1.38 (d,
3H), 2.47 (s, 3H), 3.18 (s, 3H), 3.65 (s, 3H), 4.43-4.57 (m, 1H),
5.14 (s, 2H), 7.16 (d, 1H), 7.33-7.43 (m, 2H), 7.45-7.50 (m, 1H),
7.56 (d, 1H), 7.59-7.64 (m, 1H), 8.36 (s, 1H), 8.96-9.28 (m,
1H).
Example 47
N-({3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2--
oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)a-
lanine (Racemate)
##STR00140##
171 mg (0.29 mmol) of methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-(1,3,3-trimethyl-2-
-oxo-2,3-dihydro-1H-indol-5-yl)-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-
alaninate from Example 46 were stirred in 2 ml of acetic acid and 1
ml of conc. hydrochloric acid at 120.degree. C. for 1 hour. After
cooling to RT, the reaction mixture was diluted with water and the
precipitate formed was filtered off with suction, washed with a
little MTBE and dried under reduced pressure. This gave 145 mg (85%
of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.02 min m/z=573 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.30 (s, 6H), 1.37 (d,
3H), 2.47 (s, 3H), 3.18 (s, 3H), 4.39-4.48 (m, 1H), 5.14 (s, 2H),
7.16 (d, 1H), 7.33-7.42 (m, 2H), 7.45-7.50 (m, 1H), 7.54-7.57 (m,
1H), 7.59-7.64 (m, 1H), 8.36 (s, 1H), 9.13 (d, 1H), 12.83-13.01 (m,
1H).
Example 48
Ethyl
N-({1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-met-
hyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}-
carbonyl)-2-methylalaninate
##STR00141##
118 mg (0.61 mmol) of EDC and 94 mg (0.61 mmol) of HOBt were added
to 250 mg (0.51 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tr-
ifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid from Example 26A in 2.8 ml of DMF, and the reaction mixture
was stirred at RT for 10 min. 129 mg (0.77 mmol) of ethyl
2-methylalaninate hydrochloride and 0.22 ml (1.28 mmol) of
N,N-diisopropylethylamine were then added, and the reaction mixture
was stirred at RT for a further 3 days. Water was then added, and
the mixture was filtered. The filter residue was washed with water
and dried under high vacuum at 50.degree. C. This gave 268 mg (85%
of theory) of the target compound.
LC-MS (Method 1): R.sub.t=1.20 min; MS (ESIpos): m/z=602
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.15 (t, 3H), 1.47 (s,
6H), 2.47 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 4.07 (q, 2H), 5.14
(s, 2H), 7.24-7.30 (m, 2H), 7.33-7.39 (m, 1H), 7.40-7.46 (m, 2H),
7.61 (d, 1H), 8.35 (s, 1H), 9.11 (br. s, 1H).
Example 49
N-({1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3--
(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbon-
yl)-2-methylalanine
##STR00142##
211 mg (0.35 mmol) of ethyl
N-({1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-
-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbo-
nyl)-2-methylalaninate from Example 48 in 2 ml of acetic acid and 1
ml of conc. hydrochloric acid were heated at 120.degree. C. for 45
min. After cooling to RT, the reaction mixture was diluted with
water and the precipitate formed was filtered off with suction and
dried under high vacuum. This gave 180 mg (87% of theory) of the
target compound.
LC/MS (Method 1): R.sub.t=1.00 min; m/z=574 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=1.49 (s, 6H),
2.47 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 5.14 (s, 2H), 7.24-7.31
(m, 2H), 7.33-7.44 (m, 3H), 7.54-7.65 (m, 1H), 8.35 (s, 1H),
9.07-9.33 (m, 1H), 12.68 (br. s, 1H).
Example 50
Ethyl
1-[({1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-me-
thyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl-
}carbonyl)amino]cyclobutanecarboxylate
##STR00143##
118 mg (0.61 mmol) of EDC and 94 mg (0.61 mmol) of HOBt were added
to 250 mg (0.51 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-(tr-
ifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic
acid from Example 26A in 2.8 ml of DMF, and the reaction mixture
was stirred at RT for 10 min. 138 mg (0.77 mmol) of ethyl
1-aminocyclobutanecarboxylate hydrochloride and 0.22 ml (1.28 mmol)
of N,N-diisopropylethylamine were then added, and the reaction
mixture was stirred at RT for 3 days. Water was then added, and the
mixture was filtered. The filter residue was washed with water and
dried under high vacuum at 50.degree. C. This gave 306 mg (95% of
theory) of the target compound.
LC-MS (Method 1): R.sub.t=1.21 min; MS (ESIpos): m/z=614
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.17 (t, 3H),
1.86-1.99 (m, 2H), 2.21-2.34 (m, 2H), 2.48 (s, 3H), 2.50-2.60 (m,
2H, partially obscured by DMSO signal), 3.31 (s, 3H), 3.37 (s, 3H),
4.10 (q, 2H), 5.15 (s, 2H), 7.23-7.30 (m, 2H), 7.32-7.40 (m, 1H),
7.41-7.46 (m, 2H), 7.62 (d, 1H), 8.34 (s, 1H), 9.23 (s, 1H).
Example 51
1-[({1-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl-3-
-trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbon-
yl)amino]cyclobutanecarboxylic acid
##STR00144##
50 mg (0.08 mmol) of ethyl
1-[({1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-[2-methyl--
3-(trifluoromethyl)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carb-
onyl)amino]cyclobutanecarboxylate from Example 50 were stirred in
0.5 ml of acetic acid and 0.25 ml of conc. hydrochloric acid at
120.degree. C. for 30 min. After cooling to RT, the reaction
mixture was diluted with water and the solid formed was filtered
off with suction and dried under vacuum. This gave 32 mg (66% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t: 1.02 min m/z=586 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.87-2.00 (m, 2H),
2.26-2.37 (m, 2H), 2.47 (s, 3H), 2.50-2.60 (m, 2H, partially
obscured by DMSO signal), 3.31 (s, 3H), 3.37 (s, 3H), 5.15 (s, 2H),
7.28 (s, 2H), 7.33-7.40 (m, 1H), 7.40-7.45 (m, 2H), 7.62 (d, 1H),
8.35 (s, 1H), 9.22 (s, 1H), 12.64 (br. s, 1H).
Example 52
3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin-1-
-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide
##STR00145##
300 mg (0.61 mmol) of the compound from Example 25A and 149.4 mg
(1.11 mmol) of HOBt were initially charged in 11 ml of DMF. 212 mg
(1.11 mmol) of EDC were added and the mixture was stirred at RT for
20 min. 2.3 ml of ammonia solution (35% in water) were then added.
The reaction solution was stirred at RT for 3 h and then
concentrated, and 100 ml of 1N aqueous hydrochloric acid were
added. The solid formed was filtered off with suction and dried
under high vacuum. Since, according to LC-MS, the reaction was
incomplete, the product obtained was once more dissolved in 11 ml
of DMF, and 109 mg (0.81 mmol) of HOBt and 154.7 mg (0.81 mmol) of
EDC were added. After 20 min at RT, 2 ml of ammonia solution (35%
in water) were added and the mixture was stirred at RT for 2 hours.
The mixture was concentrated again and diluted with 100 ml of 1N
aqueous hydrochloric acid, and the solid formed was filtered off
with suction and dried under high vacuum. This gave 274 mg (92% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t: 0.98 min m/z=488 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=3.43 (t, 2H),
3.80-4.01 (m, 2H), 4.96-5.28 (m, 2H), 7.11 (s, 1H), 7.31-7.41 (m,
2H), 7.45-7.50 (m, 2H), 7.60 (d, 1H), 7.67-7.72 (m, 3H), 8.12 (d,
1H), 8.33 (s, 1H).
Example 53
Methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimi-
dazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-beta-ala-
ninate
##STR00146##
Under argon, 150 mg (0.31 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from
Example 25A were initially charged in 3.75 ml of dichloromethane.
42.9 mg (0.31 mmol) of beta-alanine methyl ester hydrochloride,
98.6 mg (0.31 mmol) of
(benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and
155.3 mg (1.54 mmol) of 4-methylmorpholine were added, and the
mixture was stirred at RT for 22 h. The mixture was concentrated
and separated by preparative HPLC (Method 8). This gave 92 mg (49%
of theory) of the title compound.
LC/MS (Method 1): R.sub.t: 1.05 min m/z=574 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.47 (s, 3H),
2.56 (t, 2H, partially under the solvent signal), 3.43 (t, 2H),
3.51 (q, 2H), 3.59 (s, 3H), 3.76-3.96 (m, 2H), 5.12 (s, 2H), 7.11
(s, 1H), 7.31-7.41 (m, 2H), 7.47 (d, 2H), 7.60 (d, 1H), 7.67-7.72
(m, 2H), 8.22-8.42 (m, 1H), 8.90 (t, 1H).
Example 54
N-({3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolid-
in-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-beta-alanine
##STR00147##
58 mg (0.10 mmol) of methyl
N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazoli-
din-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-beta-alaninate
from Example 53 were dissolved in a mixture of 1 ml of glacial
acetic acid, 0.5 ml of conc. hydrochloric acid and 0.5 ml of water,
and the mixture was then stirred at 60.degree. C. for 4 h. After
cooling to RT, the mixture was diluted with 50 ml of water. After a
few minutes, the precipitate was filtered off with suction, washed
with water and dried under high vacuum. The crude product was
purified by preparative HPLC (Method 10). This gave 11 mg (19% of
theory) of the title compound.
LC-MS (Method 4): R.sub.t=2.05 min, MS (ESIpos): m/z=560
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=2.4-2.6 (partially
obscured by DMSO signal), 3.39-3.50 (m, 4H), 3.82-3.92 (m, 2H),
4.41-4.45 (m, 1H), 5.12 (s, 2H), 7.10 (s, 1H), 7.31-7.41 (m, 2H),
7.45 (d, 2H), 7.59 (d, 1H), 7.68 (d, 2H), 8.32 (s, 1H) 8.90 (t,
1H), 12.30 (br. s, 1H).
Example 55
N-Cyanomethyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxo-
imidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide
##STR00148##
Under argon, 150 mg (0.31 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
(Example 25A) were initially charged in 3.75 ml of dichloromethane.
34.4 mg (0.61 mmol) of aminoacetonitrile, 98.6 mg (0.31 mmol) of
(benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and
155.3 mg (1.54 mmol) of 4-methylmorpholine were added, and the
mixture was stirred at RT for 22 h. The mixture was diluted with 1
ml of DMF and 5 ml of acetonitrile and added to 50 ml of water. The
precipitate formed was filtered off with suction, washed with water
and dried under high vacuum. This gave 132 mg (76% of theory) of
the title compound.
LC/MS (Method 1): R.sub.t: 1.01 min m/z=527 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.48 (s, 3H),
3.43 (t, 2H), 3.86-3.93 (m, 2H), 4.29 (d, 2H), 5.02-5.23 (m, 2H),
7.11 (s, 1H), 7.31-7.37 (m, 1H), 7.40-7.44 (m, 1H), 7.49 (d, 2H),
7.60 (d, 1H), 7.67-7.73 (m, 2H), 8.34-8.46 (m, 1H), 9.15 (t,
1H).
Example 56
Methyl
N-({1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethy-
l)benzyl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)alaninate
(Racemate)
##STR00149##
100 mg (0.52 mmol) of EDC and 80 mg (0.52 mmol) of HOBt were added
to 200 mg (0.44 mmol) of
1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzyl]--
2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from
Example 27A in 2.4 ml of DMF, and the reaction mixture was stirred
at RT for 10 min. 67 mg (0.65 mmol) of DL-methyl alaninate
(racemate) and 0.11 ml (0.65 mmol) of N,N-diisopropylethylamine
were then added, and the reaction mixture was stirred at RT
overnight. Water was then added, and the mixture was filtered. The
filter residue was washed with water and dried under high vacuum at
50.degree. C. The resulting residue was purified by Versaflash.RTM.
silica gel chromatography (dichloromethane/methanol 70:1). This
gave, after concentration of the appropriate fractions and drying
under reduced pressure, 117 mg (49% of theory) of the target
compound.
LC-MS (Method 2): R.sub.t=1.22 min; MS (ESIpos): m/z=544
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.38 (d, 3H), 2.48 (s,
3H), 3.65 (s, 3H), 3.89 (s, 3H), 4.46-4.59 (m, 1H), 5.16 (s, 2H),
7.32-7.40 (m, 1H), 7.41-7.49 (m, 2H), 7.61 (d, 1H), 7.72 (d, 1H),
7.86-7.94 (m, 1H), 8.33 (s, 1H), 8.41 (s, 1H), 9.13 (d, 1H).
Example 57
N-({1-(1-Methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benzy-
l]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)alanine
(Racemate)
##STR00150##
117 mg (0.22 mmol) of methyl
N-({1-(1-methyl-1H-benzimidazol-5-yl)-3-[2-methyl-3-(trifluoromethyl)benz-
yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-DL-alaninate
(racemate) from Example 56 were initially charged in 2.4 ml of an
acetic acid/hydrochloric acid mixture (2:1 v/v), and the mixture
was stirred at 120.degree. C. for 1 h. Water was then added at RT,
and the mixture was filtered. The filter residue was washed with
water and MTBE and dried under high vacuum at 50.degree. C. This
gave 75 mg (64% of theory) of the target compound.
LC-MS (Method 1): R.sub.t=0.85 min; MS (ESIpos): m/z=530
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.37 (d, 3H), 2.48 (s,
3H), 3.95 (s, 3H), 4.39-4.49 (m, 1H), 5.16 (s, 2H), 7.33-7.40 (m,
1H), 7.42-7.47 (m, 1H), 7.53-7.59 (m, 1H), 7.59-7.65 (m, 1H), 7.84
(d, 1H), 7.97 (s, 1H), 8.43 (s, 1H), 8.70 (br. s, 1H), 9.15 (d,
1H), 12.64-13.18 (m, 1H).
Example 58
Methyl
N-{[3-(2,3-dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-te-
trahydropyrimidin-5-yl]carbonyl}-beta-alaninate
##STR00151##
Analogously to Example 44, 300 mg (0.71 mmol) of
3-(2,3-dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropy-
rimidine-5-carboxylic acid from Example 21A were reacted with 99.4
mg (0.71 mmol) of beta-alanine methyl ester hydrochloride using
TBTU and N-methylmorpholine, and the product was isolated. This
gave 261 mg (72% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.18 min; m/z=506 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.56-2.60 (m,
2H, partially under the DMSO signal), 3.51 (q, 2H), 3.59 (s, 3H),
3.81 (s, 3H), 5.14 (s, 2H), 7.07 (d, 2H), 7.21-7.26 (m, 1H),
7.28-7.36 (m, 1H), 7.46 (d, 2H), 7.58 (d, 1H), 8.31 (s, 1H), 8.86
(t, 1H).
Example 59
N-{[3-(2,3-Dichlorobenzyl)-1-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydr-
opyrimidin-5-yl]carbonyl}-beta-alanine
##STR00152##
227 mg (0.45 mmol) of the compound from Example 58 were hydrolyzed
analogously to Example 49. The product was filtered off and
additionally purified by preparative HPLC (Method 7). This gave 149
mg (68% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.04 min; m/z=492 (M+H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. [ppm]=2.46 (t, 2H),
3.47 (q, 2H), 3.81 (s, 3H), 5.13 (s, 2H), 7.04-7.10 (m, 2H),
7.20-7.26 (m, 1H), 7.28-7.35 (m, 1H), 7.43-7.49 (m, 2H), 7.56-7.60
(m, 1H), 8.31 (s, 1H), 8.86 (t, 1H), 12.29 (br. s, 1H).
Example 60
Methyl
O-tert-butyl-N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-
-[4-(2-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbo-
nyl)serinate
##STR00153##
150 mg (0.31 mmol) of
3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolidin--
1-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid from
Example 25A were initially charged in 3.75 ml of dichloromethane.
53.8 mg (0.31 mmol) of methyl O-tert-butyl-L-serinate, 98.6 mg
(0.31 mmol) of TBTU and 155 mg (1.54 mmol) of 4-methylmorpholine
were added and the mixture was stirred at RT for 22 h. The reaction
mixture was then concentrated on a rotary evaporator and the
residue was purified by preparative HPLC (Method 9). This gave 151
mg (75% of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.22 min; MS (ESIpos): m/z=646
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=1.09 (s, 9H), 2.55 (s,
3H), 3.40-3.48 (m, 2H), 3.52-3.60 (m, 1H), 3.62 (s, 3H), 3.73-3.80
(m, 1H), 3.85-3.92 (m, 2H), 4.65-4.72 (m, 1H), 5.12 (s, 2H), 7.10
(s, 1H), 7.35 (t, 1H), 7.42 (d, 1H), 7.48 (d, 2H), 7.60 (d, 1H),
7.70 (d, 2H), 8.32 (s, 1H) 9.30 (d, 1H).
Example 61
N-({3-[2-Methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-oxoimidazolid-
in-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)serine
##STR00154##
117 mg (0.181 mmol) of methyl
O-tert-butyl-N-({3-[2-methyl-3-(trifluoromethyl)benzyl]-2,4-dioxo-1-[4-(2-
-oxoimidazolidin-1-yl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-yl}carbonyl)-L-
-serinate from Example 60 were dissolved in a mixture of 2 ml of
glacial acetic acid, 1 ml of conc. hydrochloric acid and 1 ml of
water, and the mixture was then stirred at 60.degree. C. for 4 h.
After cooling to RT, the mixture was diluted with 50 ml of water.
After a few minutes, the precipitate was filtered off with suction,
washed with water and dried under high vacuum. The crude product
was purified by preparative HPLC (Method 10). This gave 39 mg (37%
of theory) of the title compound.
LC-MS (Method 4): R.sub.t=1.96 min; MS (ESIpos): m/z=576
(M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.=2.55 (s, 3H),
3.38-3.48 (m, 2H), 3.62-3.69 (m, 1H), 3.80-3.85 (m, 1H), 3.85-3.92
(m, 2H), 4.41-4.45 (m, 1H), 5.12 (s, 2H), 7.10 (s, 1H), 7.31-7.41
(m, 2H), 7.45 (d, 2H), 7.60 (d, 1H), 7.70 (d, 2H), 8.32 (s, 1H)
12.30 (br. s, 1H).
Example 62
N-Cyano-1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo--
3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydrop-
yrimidine-5-carboxamide (R Enantiomer)
##STR00155##
100 mg (0.2 mmol) of
1-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-2,4-dioxo-3-[(1R)-
-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidi-
ne-5-carboxylic acid (R enantiomer) from Example 23A, 9.2 mg (0.22
mmol) of cyanamide, 45.4 mg (0.22 mmol) of
1,3-dicyclohexylcarbodiimide and 26.9 mg (0.22 mmol) of
4-dimethylaminopyridine in 4 ml of dichloromethane were stirred at
RT overnight. The reaction solution was diluted with 20 ml of
dichloromethane and washed successively twice with 10 ml of 1N
aqueous hydrochloric acid, then with 10 ml of water and a saturated
aqueous sodium bicarbonate solution. The organic phase was
concentrated, dissolved in a acetonitrile/DMSO and separated by
preparative HPLC (Method 7).
This gave 26.4 mg (25% of theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.03 min, m/z=425 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=1.41-1.66
(m, 1H), 2.36-2.52 (m, 1H), 2.65 (dtd, 1H), 3.10-3.23 (m, 1H), 3.39
(s, 3H), 3.41 (s, 3H), 3.47 (dd, 1H), 6.63 (br. s, 1H), 6.88-7.17
(m, 3H), 7.27-7.39 (m, 2H), 7.43-7.64 (m, 1H), 8.46-8.83 (m,
1H).
Example 63
N-Cyano-1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1-
R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimi-
dine-5-carboxamide (R Enantiomer)
##STR00156##
100 mg (0.21 mmol) of
1-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(t-
rifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1,2,3,4-tetrahydropyrimidine-5--
carboxylic acid (R enantiomer) from Example 22A, 9.5 mg (0.23 mmol)
of cyanamide, 46.6 mg (0.23 mmol) of 1,3-dicyclohexylcarbodiimide
and 27.6 mg (0.23 mmol) of 4-dimethylaminopyridine in 4 ml of
dichloromethane were stirred at RT overnight. The reaction mixture
was concentrated and the residue was dissolved in DMSO and
separated by preparative HPLC (Method 6). This gave 54 mg (51% of
theory) of the title compound.
LC/MS (Method 1): R.sub.t=1.1 min., m/z=512 (M+H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.23-2.41
(m, 1H), 2.49-2.67 (m, 1H), 3.00-3.18 (m, 1H), 3.34 (s, 3H),
3.35-3.45 (m, 1H), 6.40-6.64 (m, 1H), 6.97-7.04 (m, 1H), 7.08-7.19
(m, 2H), 7.21-7.29 (m, 2H), 7.45 (t, 1H), 8.54 (s, 1H), 10.67-10.99
(m, 1H).
Example 64
1-(3-Methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-2,4-dioxo-3-[(1R)-4-(tr-
ifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-N-[(trifluoromethyl)sulfonyl]-1,-
2,3,4-tetrahydropyrimidine-5-carboxamide (R Enantiomer)
##STR00157##
At RT, 59 mg (0.39 mmol) of trifluoromethanesulfonamide were added
to a mixture of 160 mg (0.33 mmol) of the compound from Example
22A, 102 mg (049 mmol) of 1,3-dicyclohexylcarbodiimide and 44 mg
(0.36 mmol) of 4-dimethylaminopyridine in 10.3 ml of
dichloromethane. The reaction mixture was stirred at RT overnight.
The mixture was diluted with ethyl acetate and washed twice with 1M
aqueous hydrochloric acid and once with a saturated aqueous sodium
chloride solution. The organic phase was dried over sodium sulfate
and concentrated on a rotary evaporator. The crude product obtained
was purified by preparative HPLC (Method 20). This gave 52 mg (24%
of theory) of the title compound.
LC-MS (Method 1): R.sub.t=1.15 min; m/z=619 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.38-2.52
(m, 1H), 2.65 (dtd, 1H), 3.11-3.25 (m, 1H), 3.41 (s, 3H), 3.44-3.56
(m, 1H), 6.58-6.70 (m, 1H), 7.05-7.12 (m, 1H), 7.17 (d, 1H), 7.23
(br. s., 1H), 7.29-7.38 (m, 2H), 7.51-7.58 (m, 1H), 8.61 (s, 1H),
12.07 (br. s., 1H).
Example 65
2,4-Dioxo-1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-3-[(1R)-4-(trifluorometh-
yl)-2,3-dihydro-1H-inden-1-yl]-N-[(trifluoromethyl)sulfonyl]-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (R Enantiomer)
##STR00158##
Analogously to Example 64, the title compound was prepared from 160
mg (0.32 mmol) of the compound from Example 44A and 57 mg (0.38
mmol) of trifluoromethanesulfonamide. This gave 42 mg (20% of
theory).
LC-MS (Method 1): R.sub.t=1.06 min; ES(neg): m/z=631
(M-H).sup.-.
.sup.1H-NMR (400 MHz, CD.sub.2Cl.sub.2): .delta. [ppm]=2.37-2.53
(m, 1H), 2.65 (dtd, 1H), 3.11-3.24 (m, 1H), 3.42-3.57 (m, 1H), 4.06
(t, 2H), 4.49 (t, 2H), 6.58-6.70 (m, 1H), 7.28-7.41 (m, 4H),
7.50-7.58 (m, 1H), 7.71 (d, 2H), 8.61 (s, 1H), 12.10 (br. s.,
1H).
B. ASSESSMENT OF PHARMACOLOGICAL EFFICACY
The pharmacological activity of the compounds according to the
invention can be shown in the assays described below:
Abbreviations:
TABLE-US-00002 Abz-HPFHL- 1-[N-(3- Lys(Dnp)-NH.sub.2
aminobenzoyl)histidylprolylphenylalanylhistidylleucyl-
N.sup.6-(2,4-dinitrophenyl)lysine AMC 7-amido-4-methylcoumarin BNP
brain natriuretic peptide BSA bovine serum albumin CHAPS
3-[(3-cholamidopropyl)dimethylammonio]- 1-propanesulfonate HEPES
N-(2-hydroxyethyl)piperazin-N'-2-ethanesulfonic acid IC inhibition
concentration MeOSuc methoxysuccinyl NADP nicotinamide adenine
dinucleotide phosphate PBS phosphate-buffered saline solution PEG
polyethylene glycol v/v volume to volume ratio (of a solution) w/v
weight to volume ratio (of a solution)
B-1. Enzymatic Chymase Assay
The enzyme source used is recombinant human chymase (expressed in
HEK293 cells) or chymase purified from hamsters' tongues. The
substrate used for chymase is Abz-HPFHL-Lys(Dnp)-NH.sub.2. For the
assay, 1 .mu.l of a 50-fold concentrated solution of test substance
in DMSO, 24 .mu.l of enzyme solution (dilution 1:80 000 human or
1:4000 hamster) and 25 .mu.l of substrate solution (final
concentration 10 .mu.M) in assay buffer (Tris 50 mM (pH 7.5),
sodium chloride 150 mM, BSA 0.10%, Chaps 0.10%, glutathione 1 mM,
EDTA 1 mM) are combined in a white 384-hole microtitre plate
(Greiner Bio-One, Frickenhausen, Germany). The reaction is
incubated at 32 degrees for 60 min and the fluorescence emission at
465 nm after excitation at 340 nm is measured in a fluorescence
reader, for example Tecan Ultra (Tecan, Mainnedorf,
Switzerland).
One test compound is tested on the same microtitre plate in 10
different concentrations from 30 .mu.M to 1 nM in a double
determination. The data are normalized (enzyme reaction without
inhibitor=0% inhibition, all assay components without enzyme=100%
inhibition) and IC.sub.50 values are calculated using in-house
software. Compounds in the context of the invention which were
tested in this assay inhibited chymase activity with an IC.sub.50
of less than 10 .mu.M.
IC.sub.50 values representative of the compounds of the invention
are shown in Table 1 below:
TABLE-US-00003 hamster chymase Example No.: IC.sub.50 [nM] 1 4.7 2
18 3 8.7 4 48 5 29 6 6.6 7 37 8 53 9 35 12 7.6 13 1.8 14 3.5 15 2.8
16 4.6 17 2.8 18 42 19 5.8 20 22 21 32 22 7.3 23 5.5 24 85 25 30 26
44 27 130 29 13 30 3.5 31 520 32 3.1 33 4.9 34 55 35 36 36 19 37 76
38 8.1 39 16 40 12 41 12 42 9.8 43 8.1 45 25 47 4.2 48 54 49 3.6 50
39 51 3 52 94 53 180 54 63.5 55 238 57 19 59 914 60 1590 61 17 62
5.6 63 2.6
B-2. Measurement of Contraction on Isolated Aorta Rings from
Hamsters
Male Syrian hamsters (120-150 g) were euthanized with carbon
dioxide. The aorta was prepared and placed into ice-cold
Krebs-Henseleit buffer. (Composition in mmol/l: sodium chloride
112, potassium chloride 5.9, calcium chloride 2.0, magnesium
chloride 1.2, sodium dihydrogenphosphate 1.2, sodium
hydrogencarbonate 25, glucose 11.5). The aorta was cut into rings
of length 2 mm, transferred to an organ bath filled with 5 ml of
Krebs-Henseleit buffer and connected to a myograph (DMT, Denmark).
The buffer was warmed to 37.degree. C. and sparged with 95% oxygen,
5% carbon dioxide. In order to measure the isometric muscle
contraction, the aorta rings were mounted between two hooks. One of
the hooks was connected to a pressure transducer. The second hook
was movable and allowed precise setting of the initial load by a
protocol described by Mulvany and Halpern (Circulation Research
1977; 41:19-26).
Before each experiment, the responsiveness of the preparation was
tested by adding potassium-containing Krebs-Henseleit solution (50
mmol/l KCl). A synthetic peptide, angiotensin 1-18, was used to
induce contraction of the aorta rings. The angiotensin 1-18 is
converted to angiotensin II independently of ACE. Subsequently, the
aorta rings were incubated with the test substance for 20 min and
the contraction measurement was repeated. Chymase inhibition is
shown as a reduction in the contraction induced by angiotensin
1-18.
B-3. Isoprenaline-Induced Cardiac Fibrosis Model in Hamsters
For the experiments, male Syrian hamsters having a body weight of
130-160 g were used. Cardiac hypertrophy and cardiac fibrosis were
induced by a daily subcutaneous injection of 20 mg/kg isoprenaline
over 7 days. The test substance was administered orally to the
animals 2 hours before the injection of the isoprenaline. Control
groups were treated subcutaneously and orally with solvents in a
corresponding manner. At the end of the experiment, the hearts were
removed, weighed and fixed. The fibrotic tissue on the histological
sections from the hearts was marked with the aid of Sirius Red
staining. Subsequently, the fibrotic area was determined by
planimetry.
C. WORKING EXAMPLES FOR PHARMACEUTICAL COMPOSITIONS
The compounds of the invention can be converted to pharmaceutical
formulations as follows:
Tablet:
Composition:
100 mg of the compound of the invention, 50 mg of lactose
(monohydrate), 50 mg of corn starch (native), 10 mg of
polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2
mg of magnesium stearate.
Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Production:
The mixture of compound of the invention, lactose and starch is
granulated with a 5% solution (w/w) of the PVP in water. The
granules are dried and then mixed with the magnesium stearate for 5
minutes. This mixture is compressed in a conventional tabletting
press (see above for format of the tablet). The guide value used
for the pressing is a pressing force of 15 kN.
Suspension for Oral Administration:
Composition:
1000 mg of the compound of the invention, 1000 mg of ethanol (96%),
400 mg of Rhodigel.RTM. (xanthan gum from FMC, Pennsylvania, USA)
and 99 g of water.
10 ml of oral suspension correspond to a single dose of 100 mg of
the compound of the invention.
Production:
The Rhodigel is suspended in ethanol; the compound of the invention
is added to the suspension. The water is added while stirring. The
mixture is stirred for about 6 h before swelling of the Rhodigel is
complete.
Solution for Oral Administration:
Composition:
500 mg of the compound of the invention, 2.5 g of polysorbate and
97 g of polyethylene glycol 400. 20 g of oral solution correspond
to a single dose of 100 mg of the compound of the invention.
Production:
The compound of the invention is suspended in the mixture of
polyethylene glycol and polysorbate with stirring. The stirring
operation is continued until dissolution of the compound of the
invention is complete.
i.v. Solution:
The compound of the invention is dissolved in a concentration below
the saturation solubility in a physiologically acceptable solvent
(e.g. isotonic saline solution, glucose solution 5% and/or PEG 400
solution 30%). The solution is subjected to sterile filtration and
dispensed into sterile and pyrogen-free injection vessels.
* * * * *